Journal articles: 'Calcium and integrin binding protein'

1

Tsuboi, Shigeru. "Calcium Integrin-binding Protein Activates Platelet Integrin αIIbβ3." Journal of Biological Chemistry 277, no. 3 (November 9, 2001): 1919–23. http://dx.doi.org/10.1074/jbc.m110643200.

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Dickens, Olivia, Raul Mendez-Giraldez, and Nikolay Dokholyan. "Modeling the Calcium and Integrin Binding Protein 2." Biophysical Journal 108, no. 2 (January 2015): 213a. http://dx.doi.org/10.1016/j.bpj.2014.11.1178.

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3

Hodivala, KJ, and FM Watt. "Evidence that cadherins play a role in the downregulation of integrin expression that occurs during keratinocyte terminal differentiation." Journal of Cell Biology 124, no. 4 (February 15, 1994): 589–600. http://dx.doi.org/10.1083/jcb.124.4.589.

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In epidermis the onset of terminal differentiation normally coincides with inhibition of integrin function and expression, thereby ensuring that differentiating cells are selectively expelled from the basal layer. However, when stratification of cultured human epidermal keratinocytes is prevented by reducing the calcium concentration of the medium to 0.1 mM, keratinocytes initiate terminal differentiation while still attached to the culture substrate. We have examined the mechanism by which differentiating keratinocytes adhere to extracellular matrix proteins in low calcium medium and the consequences of inducing stratification by raising the calcium ion concentration to 1.8 mM (Standard Medium). In low calcium medium keratinocytes co-expressed integrins and terminal differentiation markers such as involucrin and peanut lectin-binding glycoproteins: differentiating cells contained integrin mRNA, synthesized integrin proteins de novo and expressed functional mature integrins. There were no differences in integrin synthesis, maturation or break down in low calcium or standard medium, although the level of beta 1 integrins on the surface of proliferating cells was higher in standard medium. Within 6 h of transfer from low calcium to standard medium integrin mRNA was no longer detectable in terminally differentiating cells, integrins were being lost from the cell surface, and selective migration out of the basal layer had begun. Antibodies to P- and E-cadherin, which block calcium-induced stratification, prevented the selective loss of integrin mRNA and protein from terminally differentiating cells. This suggests that cadherins may play a role in the down-regulation of integrin expression that is associated with terminal differentiation.

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Huang, Hao, Joel N. Bogstie, and Hans J. Vogel. "Biophysical and structural studies of the human calcium- and integrin-binding protein family: understanding their functional similarities and differences." Biochemistry and Cell Biology 90, no. 5 (October 2012): 646–56. http://dx.doi.org/10.1139/o2012-021.

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The human calcium- and integrin-binding protein 1 (CIB1) plays important roles in various cellular functions. In this study, three other members of this protein family (CIB2–4: CIB2, CIB3, and CIB4) were purified and subsequently characterized using biophysical and structural approaches. As expected from sequence alignments, CIB2–4 were shown to bind calcium (Ca2+) and magnesium (Mg2+) ions. Binding of Ca2+ or Mg2+ ions changes the secondary structure of CIB2–4 and the exposure of hydrophobic surface area. Ca2+ and Mg2+ ions also stabilize the tertiary structures for CIB2 and CIB3. Through in vitro binding experiments, we show that CIB2 can interact with the integrin αIIb cytoplasmic domain and the integrin α7b membrane-proximal fragment. Fluorescence experiments using a 7-azatryptophan labeled peptide demonstrate that CIB2, CIB3, and CIB4 are binding partners for the integrin αIIb subunit, which suggests that they are potentially involved in regulating integrin αIIb subunit activation. The distinct responses of αIIb to the different CIB3 and CIB4 metal (Ca2+ and Mg2+) binding states imply a potential connection between the calcium and integrin signaling pathways.

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Vallar, Laurent, Chantal Melchior, Sébastien Plançon, Hervé Drobecq, Guy Lippens, Véronique Regnault, and Nelly Kieffer. "Divalent Cations Differentially Regulate Integrin αIIbCytoplasmic Tail Binding to β3and to Calcium- and Integrin-binding Protein." Journal of Biological Chemistry 274, no. 24 (June 11, 1999): 17257–66. http://dx.doi.org/10.1074/jbc.274.24.17257.

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Yamniuk, Aaron P., and Hans J. Vogel. "Calcium- and magnesium-dependent interactions between calcium- and integrin-binding protein and the integrin αIIb cytoplasmic domain." Protein Science 14, no. 6 (January 1, 2009): 1429–37. http://dx.doi.org/10.1110/ps.041312805.

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Arora, Pamela D., Michael Glogauer, Andras Kapus, David J. Kwiatkowski, and Christopher A. McCulloch. "Gelsolin Mediates Collagen Phagocytosis through a Rac-dependent Step." Molecular Biology of the Cell 15, no. 2 (February 2004): 588–99. http://dx.doi.org/10.1091/mbc.e03-07-0468.

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The role of gelsolin, a calcium-dependent actin-severing protein, in mediating collagen phagocytosis, is not defined. We examined α2β1 integrin-mediated phagocytosis in fibroblasts from wild-type (WT) and gelsolin knockout (Gsn-) mice. After initial contact with collagen beads, collagen binding and internalization were 60% lower in Gsn- than WT cells. This deficiency was restored by transfection with gelsolin or with β1 integrin-activating antibodies. WT cells showed robust rac activation and increased [Ca2+]i during early contact with collagen beads, but Gsn- cells showed very limited responses. Transfected gelsolin in Gsn- cells restored rac activation after collagen binding. Transfection of Gsn- cells with active rac increased collagen binding to WT levels. Chelation of intracellular calcium inhibited collagen binding and rac activation, whereas calcium ionophore induced rac activation in WT and Gsn- cells. We conclude that the ability of gelsolin to remodel actin filaments is important for collagen-induced calcium entry; calcium in turn is required for rac activation, which subsequently enhances collagen binding to unoccupied α2β1 integrins.

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Yamniuk, Aaron P., Leonard T. Nguyen, Tung T. Hoang, and Hans J. Vogel. "Metal Ion Binding Properties and Conformational States of Calcium- and Integrin-Binding Protein†." Biochemistry 43, no. 9 (March 2004): 2558–68. http://dx.doi.org/10.1021/bi035432b.

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9

SHOCK, David D., Ulhas P. NAIK, Julia E. BRITTAIN, Suresh K. ALAHARI, John SONDEK, and Leslie V. PARISE. "Calcium-dependent properties of CIB binding to the integrin αIIb cytoplasmic domain and translocation to the platelet cytoskeleton." Biochemical Journal 342, no. 3 (September 5, 1999): 729–35. http://dx.doi.org/10.1042/bj3420729.

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The αIIbβ3 integrin receives signals in agonist-activated platelets, resulting in its conversion to an active conformation that binds fibrinogen, thereby mediating platelet aggregation. Fibrinogen binding to αIIbβ3 subsequently induces a cascade of intracellular signalling events. The molecular mechanisms of this bi-directional αIIbβ3-mediated signalling are unknown but may involve the binding of proteins to the integrin cytoplasmic domains. We reported previously the sequence of a novel 22-kDa, EF-hand-containing, protein termed CIB (calcium- and integrin-binding protein) that interacts specifically with the αIIb cytoplasmic domain in the yeast two-hybrid system. Further analysis of numerous tissues and cell lines indicated that CIB mRNA and protein are widely expressed. In addition, isothermal titration calorimetry indicated that CIB binds to an αIIb cytoplasmic-domain peptide in a Ca2+-dependent manner, with moderate affinity (Kd, 700 nM) and 1:1 stoichiometry. In aggregated platelets, endogenous CIB and αIIbβ3 translocate to the Triton X-100-insoluble cytoskeleton in a parallel manner, demonstrating that the cellular localization of CIB is regulated, potentially by αIIbβ3. Thus CIB may contribute to integrin-related functions by mechanisms involving Ca2+-modulated binding to the αIIb cytoplasmic domain and changes in intracellular distribution.

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Sekimoto, Hiroko, Jodi Eipper-Mains, Sunthorn Pond-Tor, and Charlotte M. Boney. "αvβ3 Integrins and Pyk2 Mediate Insulin-Like Growth Factor I Activation of Src and Mitogen-Activated Protein Kinase in 3T3-L1 Cells." Molecular Endocrinology 19, no. 7 (July 1, 2005): 1859–67. http://dx.doi.org/10.1210/me.2004-0481.

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Abstract IGF-I stimulates cell growth through interaction of the IGF receptor with multiprotein signaling complexes. However, the mechanisms of IGF-I receptor-mediated signaling are not completely understood. We have previously shown that IGF-I-stimulated 3T3-L1 cell proliferation is dependent on Src activation of the ERK-1/2 MAPK pathway. We hypothesized that IGF-I activation of the MAPK pathway is mediated through integrin activation of Src-containing signaling complexes. The disintegrin echistatin decreased IGF-I phosphorylation of Src and MAPK, and blocking antibodies to αv and β3 integrin subunits inhibited IGF-I activation of MAPK, suggesting that αvβ3 integrins mediate IGF-I mitogenic signaling. IGF-I increased ligand binding to αvβ3 as detected by immunofluorescent staining of ligand-induced binding site antibody and stimulated phosphorylation of the β3 subunit, consistent with inside-out activation of αvβ3 integrins. IGF-I increased tyrosine phosphorylation of the focal adhesion kinase (FAK) Pyk2 (calcium-dependent proline-rich tyrosine kinase-2) to a much greater extent than FAK, and increased association of Src with Pyk2 but not FAK. The intracellular calcium chelator BAPTA prevented IGF-I phosphorylation of Pyk2, Src, and MAPK, suggesting that IGF-I activation of Pyk2 is calcium dependent. Transient transfection with a dominant-negative Pyk2, which lacks the autophosphorylation and Src binding site, decreased IGF-I activation of MAPK, but no inhibition was seen with transfected wild-type Pyk2. These results indicate that IGF-I signaling to MAPK is dependent on inside-out activation of αvβ3 integrins and integrin-facilitated multiprotein complex formation involving Pyk2 activation and association with Src.

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Hui, Ling, Chaoneng Ji, Bin Hui, Tongde Lv, Xiaoqin Ha, Jinsheng Yang, and Wenqin Cai. "The oncoprotein LMO3 interacts with calcium- and integrin-binding protein CIB." Brain Research 1265 (April 2009): 24–29. http://dx.doi.org/10.1016/j.brainres.2009.02.021.

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12

Bouvard, D., A. Molla, and M. R. Block. "Calcium/calmodulin-dependent protein kinase II controls alpha5beta1 integrin-mediated inside-out signaling." Journal of Cell Science 111, no. 5 (March 1, 1998): 657–65. http://dx.doi.org/10.1242/jcs.111.5.657.

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Fibronectin binding on alpha5beta1 integrin is strictly dependent on intracellular calcium. Using an in vitro assay, we previously found that either calcineurin inhibitors or a blocking calcineurin monoclonal antibody added to cell lysates completely abolished the fibronectin/integrin interaction, which suggested that the activity of calcineurin, a calcium/calmodulin-dependent phosphatase, was required to counteract some kinase activity and maintain the high affinity state of alpha5beta1. In this paper, we show that blocking of the calcium/calmodulin kinase II (CaMKII) activity with the specific inhibitor KN-62 or with its pseudosubtrate Autocamtide-2 preserved the high affinity state of the integrin even under experimental conditions that inhibit calcineurin. Conversely, the addition of purified CaMKII to the cell lysate inhibited alpha5beta1 binding to fibronectin in vitro. Consistent with these results, cell adhesion on fibronectin was stimulated by KN-62. Moreover, Scatchard analysis of fibronectin binding on CHO cells revealed that KN-62 decreased the Kd value from 0.3 to 0.05 microM. Finally the expression of exogenous constitutively active CaMKII resulted in a dramatic defect in cell adhesion with no significant modification in alpha5beta1 cell surface expression. In summary our results demonstrate that CaMKII controls the affinity state of the integrin alpha5beta1 in vitro and in living cells.

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13

Wang, Xianwang, Xiaochun Peng, Xueqing Zhang, Hanyi Xu, Chengbiao Lu, Lian Liu, Jiaxing Song, and Yingjie Zhang. "The Emerging Roles of CIB1 in Cancer." Cellular Physiology and Biochemistry 43, no. 4 (2017): 1413–24. http://dx.doi.org/10.1159/000481873.

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Calcium and integrin-binding protein 1 (CIB1) is an EF-hand calcium binding protein, which is involved in many cellular processes, including calcium signaling, cell survival and proliferation, cell migration, cell adhesion and apoptosis. A number of studies have found that CIB1 is ubiquitously expressed and is related to various human diseases, such as cancer, Alzheimer’s disease (AD), cardiac hypertrophy and male infertility. The mechanism of CIB1 in human diseases is still not clear, although multiple functions of CIB1 are modulated by interacting with numerous interacting partners. As a calcium binding protein, the roles of CIB1 in calcium signaling by binding calcium or modulating some key modulators, such as calcineurin, integrin, inositol 1,4,5-trisphosphate receptor (IP3R) and taste 1 receptor member 2 (TAS1R2). The tumor promoting mechanisms of CIB1 have been described in different aspects, including promoting tumor cell cycle and proliferation, inhibiting tumor cell apoptosis, and mediating tumor cell migration and angiogenesis. In addition, multiple functions of CIB1, such as neural development, taste or gustation functions, and virus infection are also elucidated. These recent advances have significantly expanded our understanding of the knowledge of CIB1 and highlighted the potential mechanisms of CIB1 in tumor progression.

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14

Newton, Rebecca A., and Nancy Hogg. "The Human S100 Protein MRP-14 Is a Novel Activator of the β2 Integrin Mac-1 on Neutrophils." Journal of Immunology 160, no. 3 (February 1, 1998): 1427–35. http://dx.doi.org/10.4049/jimmunol.160.3.1427.

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Abstract The 14-kDa myeloid-related protein (MRP-14) and its heterodimeric partner, MRP-8, are members of the S100 family of calcium-binding proteins (S100A9 and S100A8, respectively). Their importance in neutrophil function is implied by their unusual abundance in neutrophil cytosol (∼40% of cytosolic protein). Previous work from our laboratory has demonstrated the extracellular association of these proteins with vascular endothelium adjacent to transmigrating leukocytes. We report here a function for MRP-14 as a stimulator of neutrophil adhesion mediated by the β2 integrin, Mac-1. MRP-14 is an affinity regulator of Mac-1 because it promotes binding of soluble ligand and expression of an “activation reporter” epitope of high affinity β2 integrins recognized by mAb24. The activity of MRP-14 is confined to regulating integrin function because, unlike other inflammatory agonists, there was no release of L-selectin, up-regulation of cytosolic Mac-1, or induction of neutrophil respiratory burst or calcium flux. Furthermore, MRP-14 does not act as a chemoattractant or cause alterations in cell shape or cytoskeleton. MRP-8 has a regulatory role in MRP-14 activity, inhibiting the adhesion induced by MRP-14 through the formation of the heterodimer. In terms of mechanism of action, MRP-14 does not increase Mac-1 function by direct binding to this integrin but recognizes a distinct receptor on neutrophils. This receptor interaction is pertussis toxin sensitive, indicating that MRP-14-generated signals leading to a Mac-1 affinity increase are heterotrimeric G protein dependent. We postulate that MRP-14 and MRP-8 are important in vivo candidates for the regulated adhesion of neutrophils through control of Mac-1 activity.

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15

Kostyak, John C., Meghna U. Naik, and Ulhas P. Naik. "Calcium- and integrin-binding protein 1 regulates megakaryocyte ploidy, adhesion, and migration." Blood 119, no. 3 (January 19, 2012): 838–46. http://dx.doi.org/10.1182/blood-2011-04-346098.

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Abstract Megakaryocytes are large, polyploid cells that produce platelets. We have previously reported that calcium- and integrin-binding protein 1 (CIB1) regulates endomitosis in Dami cells. To further characterize the role of CIB1 in megakaryopoiesis, we used a Cib1−/− mouse model. Cib1−/− mice have more platelets and BM megakaryocytes than wild-type (WT) controls (P < .05). Furthermore, subsequent analysis of megakaryocyte-CFU production revealed an increase with Cib1 deletion compared with WT (P < .05). In addition, BM from Cib1−/− mice, cultured with thrombopoietin (TPO) for 24 hours, produced more highly polyploid megakaryocytes than WT BM (P < .05). Subsequent analysis of TPO signaling revealed enhanced Akt and ERK1/2 phosphorylation, whereas FAKY925 phosphorylation was reduced in Cib1−/− megakaryocytes treated with TPO. Conversely, platelet recovery in Cib1−/− mice after platelet depletion was attenuated compared with WT (P < .05). This could be the result of impaired adhesion and migration, as adhesion to fibrinogen and fibronectin and migration toward an SDF-1α gradient were reduced in Cib1−/− megakaryocytes compared with WT (P < .05). In addition, Cib1−/− megakaryocytes formed fewer proplatelets compared with WT (P < .05), when plated on fibrinogen. These data suggest that CIB1 plays a dual role in megakaryopoiesis, initially by negatively regulating TPO signaling and later by augmenting proplatelet production.

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Huang, Hao, and Hans J. Vogel. "Structural Basis for the Activation of Platelet Integrin αIIbβ3 by Calcium- and Integrin-Binding Protein 1." Journal of the American Chemical Society 134, no. 8 (February 16, 2012): 3864–72. http://dx.doi.org/10.1021/ja2111306.

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17

Balasubramanian, Lavanya, Abu Ahmed, Chun-Min Lo, James S. K. Sham, and Kay-Pong Yip. "Integrin-mediated mechanotransduction in renal vascular smooth muscle cells: activation of calcium sparks." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 293, no. 4 (October 2007): R1586—R1594. http://dx.doi.org/10.1152/ajpregu.00025.2007.

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Integrins are transmembrane heterodimeric proteins that link extracellular matrix (ECM) to cytoskeleton and have been shown to function as mechanotransducers in nonmuscle cells. Synthetic integrin-binding peptide triggers Ca2+ mobilization and contraction in vascular smooth muscle cells (VSMCs) of rat afferent arteriole, indicating that interactions between the ECM and integrins modulate vascular tone. To examine whether integrins transduce extracellular mechanical stress into intracellular Ca2+ signaling events in VSMCs, unidirectional mechanical force was applied to freshly isolated renal VSMCs through paramagnetic beads coated with fibronectin (natural ligand of α5β1-integrin in VSMCs). Pulling of fibronectin-coated beads with an electromagnet triggered Ca2+ sparks, followed by global Ca2+ mobilization. Paramagnetic beads coated with low-density lipoprotein, whose receptors are not linked to cytoskeleton, were minimally effective in triggering Ca2+ sparks and global Ca2+ mobilization. Preincubation with ryanodine, cytochalasin-D, or colchicine substantially reduced the occurrence of Ca2+ sparks triggered by fibronectin-coated beads. Binding of VSMCs with antibodies specific to the extracellular domains of α5- and β1-integrins triggered Ca2+ sparks simulating the effects of fibronectin-coated beads. Preincubation of microperfused afferent arterioles with ryanodine or integrin-specific binding peptide inhibited pressure-induced myogenic constriction. In conclusion, integrins transduce mechanical force into intracellular Ca2+ signaling events in renal VSMCs. Integrin-mediated mechanotransduction is probably involved in myogenic response of afferent arterioles.

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Temple, Brenda R., Holly R. Gentry, Jan C. DeNofrio, Weiping Yuan, and Leslie V. Parise. "Characterization of calcium- and integrin-binding protein 1 (CIB1) knockout platelets: Potential compensation by CIB family members." Thrombosis and Haemostasis 100, no. 05 (2008): 847–56. http://dx.doi.org/10.1160/th08-06-0351.

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SummaryPlatelet aggregation requires activation of the αIIbβ3 integrin,an event regulated by the integrin cytoplasmic tails. CIB1 binds to the cytoplasmic tail of the integrin αIIb subunit. Previous overexpression and knockdown studies in murine megakaryocytes demonstrated that CIB1 inhibits integrin αIIbβ3 activation.Here we analyzed Cib1-/- mice to determine the function of CIB1 in platelets in vitro and in vivo. We found that although these mice had no overt platelet phenotype, mRNA level of CIB1 homolog CIB3 was increased in Cib1-/- megakaryocytes. In vitro binding experiments showed that recombinant CIB1, -2 and -3 bound specifically to an αIIb cytoplasmic tail peptide. Subsequent protein modeling experiments indicated that CIBs 1–3 each have a highly conserved hydrophobic binding pocket. Therefore, the potential exists for compensation for the loss of CIB1 by these CIB family members, thereby preventing pathologic thrombus formation in Cib1-/- mice.

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Namyanja, Monica, Zhi-Shen Xu, Claire Mack Mugasa, Zhao-Rong Lun, Enock Matovu, Zhengjun Chen, and George W. Lubega. "Preliminary evaluation of a Trypanosoma brucei FG-GAP repeat containing protein of mitochondrial localization." AAS Open Research 2 (November 19, 2019): 165. http://dx.doi.org/10.12688/aasopenres.12986.1.

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Background: Trypanosoma brucei, a causative agent of African Trypanosomiasis, is known to cross the blood brain barrier during the second stage of the disease. It was previously suggested that this parasite crosses the blood brain barrier in a manner similar to that of lymphocytes. This would imply that trypanosomes possess integrins that are required to interact with adhesion molecules located on the blood brain barrier microvascular endothelial cells, as a first step in traversal. To date, no T. brucei integrin has been described. However, one T. brucei putative FG-GAP repeat containing protein (typical of integrins) encoded by the Tb927.11.720 gene, was predicted to be involved in cell-cell/cell-matrix adhesion. Therefore, this study sought to characterize a putative FG-GAP repeat containing protein (FG-GAP RCP) and to determine its cellular localization as a basis for further exploration of its potential role in cell-cell or cell-matrix adhesion. Methods: In this study, we successfully cloned, characterized, expressed and localized this protein using antibodies we produced against its VCBS domain in T. brucei. Results: Contrary to what we initially suspected, our data showed that this protein is localized to the mitochondria but not the plasma membrane. Our data showed that it contains putative calcium binding motifs within the FG-GAP repeats suggesting it could be involved in calcium signaling/binding in the mitochondrion of T. brucei. Conclusion: Based on its localization we conclude that this protein is unlikely to be a trypanosomal integrin and thus that it may not be involved in traversal of the blood brain barrier. However, it could be involved in calcium signaling in the mitochondrion.

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Freeman, Thomas C., Justin L. Black, Holly G. Bray, Onur Dagliyan, Yi I. Wu, Ashutosh Tripathy, Nikolay V. Dokholyan, Tina M. Leisner, and Leslie V. Parise. "Identification of Novel Integrin Binding Partners for Calcium and Integrin Binding Protein 1 (CIB1): Structural and Thermodynamic Basis of CIB1 Promiscuity." Biochemistry 52, no. 40 (September 25, 2013): 7082–90. http://dx.doi.org/10.1021/bi400678y.

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Puhl, Ana C., Jonathan W. Bogart, Victoria A. Haberman, Jacob E. Larson, Andre S. Godoy, Jacqueline L. Norris-Drouin, Stephanie H. Cholensky, et al. "Discovery and Characterization of Peptide Inhibitors for Calcium and Integrin Binding Protein 1." ACS Chemical Biology 15, no. 6 (May 8, 2020): 1505–16. http://dx.doi.org/10.1021/acschembio.0c00144.

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Yamniuk, Aaron P., Dylan M. Silver, Kathryn L. Anderson, Stephen R. Martin, and Hans J. Vogel. "Domain Stability and Metal-Induced Folding of Calcium- and Integrin-Binding Protein 1†." Biochemistry 46, no. 24 (June 2007): 7088–98. http://dx.doi.org/10.1021/bi700200z.

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23

Berger, Bryan W., Chad J. Blamey, Ulhas P. Naik, Brian J. Bahnson, and Abraham M. Lenhoff. "Roles of Additives and Precipitants in Crystallization of Calcium- and Integrin-Binding Protein." Crystal Growth & Design 5, no. 4 (July 2005): 1499–507. http://dx.doi.org/10.1021/cg050013u.

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Hyduk, Sharon J., Jason R. Chan,, Stewart T. Duffy, Mian Chen, Mark D. Peterson, Thomas K. Waddell, Genevieve C. Digby, Katalin Szaszi, Andras Kapus, and Myron I. Cybulsky. "Phospholipase C, calcium, and calmodulin are critical for α4β1 integrin affinity up-regulation and monocyte arrest triggered by chemoattractants." Blood 109, no. 1 (September 7, 2006): 176–84. http://dx.doi.org/10.1182/blood-2006-01-029199.

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Abstract During inflammation, monocytes roll on activated endothelium and arrest after stimulation by proteoglycan-bound chemokines and other chemoattractants. We investigated signaling pathways downstream of G protein–coupled receptors (GPCRs) that are relevant to α4β1 integrin affinity up-regulation using formyl peptide receptor-transfected U937 cells stimulated with fMLP or stromal-derived factor-1α and human peripheral blood monocytes stimulated with multiple chemokines or chemoattractants. The up-regulation of soluble LDV peptide or vascular cell adhesion molecule-1 (VCAM-1) binding by these stimuli was critically dependent on activation of phospholipase C (PLC), inositol 1,4,5-triphosphate receptors, increased intracellular calcium, influx of extracellular calcium, and calmodulin, suggesting that this signaling pathway is required for α4 integrins to assume a high-affinity conformation. In fact, a rise in intracellular calcium following treatment with thapsigargin or ionomycin was sufficient to induce binding of ligand. Blockade of p44/42 and p38 mitogen-activated protein (MAP) kinases, phosphoinositide 3-kinase, or protein kinase C (PKC) signaling did not inhibit chemoattractant-induced LDV or VCAM-1 binding. However, activation of PKC by phorbol ester up-regulated α4β1 affinity with kinetics distinct from those of GPCR signaling. A critical role for PLC and calmodulin was also established for leukocyte arrest and adhesion strengthening.

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Dal Cortivo, Giuditta, and Daniele Dell’Orco. "Calcium- and Integrin-Binding Protein 2 (CIB2) in Physiology and Disease: Bright and Dark Sides." International Journal of Molecular Sciences 23, no. 7 (March 24, 2022): 3552. http://dx.doi.org/10.3390/ijms23073552.

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Calcium- and integrin-binding protein 2 (CIB2) is a small EF-hand protein capable of binding Mg2+ and Ca2+ ions. While its biological function remains largely unclear, an increasing number of studies have shown that CIB2 is an essential component of the mechano-transduction machinery that operates in cochlear hair cells. Mutations in the gene encoding CIB2 have been associated with non-syndromic deafness. In addition to playing an important role in the physiology of hearing, CIB2 has been implicated in a multitude of very different processes, ranging from integrin signaling in platelets and skeletal muscle to autophagy, suggesting extensive functional plasticity. In this review, we summarize the current understanding of biochemical and biophysical properties of CIB2 and the biological roles that have been proposed for the protein in a variety of processes. We also highlight the many molecular aspects that remain unclarified and deserve further investigation.

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Naik, Ulhas P., Pankaj M. Patel, and Leslie V. Parise. "Identification of a Novel Calcium-binding Protein That Interacts with the Integrin αIIbCytoplasmic Domain." Journal of Biological Chemistry 272, no. 8 (February 21, 1997): 4651–54. http://dx.doi.org/10.1074/jbc.272.8.4651.

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Notarangelo, Luigi D. "HPV: CIB1 is for EVER and EVER." Journal of Experimental Medicine 215, no. 9 (August 1, 2018): 2229–31. http://dx.doi.org/10.1084/jem.20181207.

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In this issue, de Jong et al. (https://doi.org/10.1084/jem.20170308) identify bi-allelic loss-of-expression, loss-of-function mutations of the calcium- and integrin-binding protein 1 (CIB1) gene as a new cause of epidermodysplasia verruciformis (EV) and demonstrate that the CIB1 interacts with the EVER1 and EVER2 proteins to form a complex involved in keratinocyte-intrinsic immune response to human β-papillomaviruses (β-HPVs).

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Chao, Jun-Tzu, Peichun Gui, Gerald W. Zamponi, George E. Davis, and Michael J. Davis. "Spatial association of the Cav1.2 calcium channel with α5β1-integrin." American Journal of Physiology-Cell Physiology 300, no. 3 (March 2011): C477—C489. http://dx.doi.org/10.1152/ajpcell.00171.2010.

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Engagement of α5β1-integrin by fibronectin (FN) acutely enhances Cav1.2 channel (CaL) current in rat arteriolar smooth muscle and human embryonic kidney cells (HEK293-T) expressing CaL. Using coimmunoprecipitation strategies, we show that coassociation of CaL with α5- or β1-integrin in HEK293-T cells is specific and depends on cell adhesion to FN. In rat arteriolar smooth muscle, coassociations between CaL and α5β1-integrin and between CaL and phosphorylated c-Src are also revealed and enhanced by FN treatment. Using site-directed mutagenesis of CaL heterologously expressed in HEK293-T cells, we identified two regions of CaL required for these interactions: 1) COOH-terminal residues Ser1901 and Tyr2122, known to be phosphorylated by protein kinase A (PKA) and c-Src, respectively; and 2) two proline-rich domains (PRDs) near the middle of the COOH terminus. Immunofluorescence confocal imaging revealed a moderate degree of wild-type CaL colocalization with β1-integrin on the plasma membrane. Collectively, our results strongly suggest that 1) upon ligation by FN, CaL associates with α5β1-integrin in a macromolecular complex including PKA, c-Src, and potentially other protein kinases; 2) phosphorylation of CaL at Y2122 and/or S1901 is required for association of CaL with α5β1-integrin; and 3) c-Src, via binding to PRDs that reside in the II–III linker region and/or the COOH terminus of CaL, mediates current potentiation following α5β1-integrin engagement. These findings provide new evidence for how interactions between α5β1-integrin and FN can modulate CaL entry and consequently alter the physiological function of multiple types of excitable cells.

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Yuan, Weiping, Tina M. Leisner, Andrew W. McFadden, Zhengyan Wang, Mark K. Larson, Shantres Clark, Christel Boudignon-Proudhon, Stephen C. T. Lam, and Leslie V. Parise. "CIB1 is an endogenous inhibitor of agonist-induced integrin αIIbβ3 activation." Journal of Cell Biology 172, no. 2 (January 16, 2006): 169–75. http://dx.doi.org/10.1083/jcb.200505131.

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In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. This process contributes to both normal hemostasis and thrombosis. Activation of αIIbβ3 is believed to occur in part via engagement of the β3 cytoplasmic tail with talin; however, the role of the αIIb tail and its potential binding partners in regulating αIIbβ3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the αIIb tail, is an endogenous inhibitor of αIIbβ3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced αIIbβ3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to αIIbβ3, thus providing a model for tightly controlled regulation of αIIbβ3 activation.

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Leung-Hagesteijn, C. Y., K. Milankov, M. Michalak, J. Wilkins, and S. Dedhar. "Cell attachment to extracellular matrix substrates is inhibited upon downregulation of expression of calreticulin, an intracellular integrin alpha-subunit-binding protein." Journal of Cell Science 107, no. 3 (March 1, 1994): 589–600. http://dx.doi.org/10.1242/jcs.107.3.589.

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We have demonstrated recently that calreticulin, an intracellular calcium-binding protein, can interact with the alpha-subunits of integrin receptors via the highly conserved KXGFFKR amino acid sequence present in the cytoplasmic domains of all integrin alpha-subunits (Rojiani et al. (1991) Biochemistry 30, 9859–9866). Here we demonstrate that calreticulin can be co-localized by immunofluorescence as well as co-purified with integrins, that recombinant calreticulin can also interact with integrins, and that the interaction occurs predominantly via the N-domain of calreticulin, to a much lesser extent with the C-domain, but not at all with the proline-rich P-domain. To demonstrate a physiological role for the interaction of calreticulin with integrins, calreticulin expression was downregulated by treating cells with antisense oligonucleotides designed to inhibit the initiation of translation of calreticulin. Antisense oligonucleotides, but not sense or non-sense oligonucleotides, inhibited attachment and spreading of cells cultured in the presence of fetal bovine serum, and also of cells plated on individual extracellular matrix substrates in the absence of serum. The antisense oligonucleotide inhibited cell proliferation of anchorage-dependent cells slightly, but there was no effect on cell viability. The effect on cell attachment was similar to that achieved by treating cells with an antisense oligonucleotide designed to inhibit translation of the integrin alpha 3 subunit, which resulted in the inhibition of cell attachment to alpha 3 beta 1-specific substrates. The effect of the antisense calreticulin oligonucleotide on cell attachment was demonstrated to be integrin-mediated since antisense calreticulin treatment of Jurkat cells abrogated the stimulation of collagen cell attachment achieved by attachment-stimulating signalling anti-alpha 2 (JBS2) and anti-beta 1 (21C8) antibodies. The oligonucleotides did not affect the rate of cell proliferation of these cells. These results demonstrate a fundamental role of calreticulin in cell-extracellular matrix interactions.

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Tsuboi, Shigeru. "A Disease Mechanism Underlying Bleeding in Wiskott-Aldrich Syndrome." Clinical medicine. Blood disorders 1 (January 2008): CMBD.S536. http://dx.doi.org/10.4137/cmbd.s536.

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The Wiskott-Aldrich Syndrome (WAS) is an × chromosome-linked immunodeficiency disorder. The most common symptom in WAS is bleeding. Several clinical investigations indicate that low platelet counts and defective platelet aggregation are the major causes of bleeding in WAS patients. However, the molecular bases underlying these defects are unclear. This study focuses on the molecular mechanism of defective platelet aggregation of WAS patients. The gene responsible for WAS encodes WAS protein (WASP). The mutations or deletion of WASP causes various functional defects in hematopoietic cells. We previously showed that binding of WASP to calcium- and integrin-binding protein (CIB) is required for activation of platelet integrin, αIIbβ3. I here demonstrate that blocking WASP binding to CIB reduces binding of talin to the β3 cytoplasmic tail, resulting in impaired activation of αIIbβ3. Impaired αIIbβ3 activation causes defective platelet aggregation, resulting in bleeding. This finding suggests a potential disease mechanism underlying bleeding seen in WAS patients.

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Blamey, Chad J., Christopher Ceccarelli, Ulhas P. Naik, and Brian J. Bahnson. "The crystal structure of calcium- and integrin-binding protein 1: Insights into redox regulated functions." Protein Science 14, no. 5 (May 2005): 1214–21. http://dx.doi.org/10.1110/ps.041270805.

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Fang, Xiang-Dong, Chun Chen, Qi Wang, Jian-Xin Gu, and Cheng-Wu Chi. "The Interaction of the Calcium- and Integrin-Binding Protein (CIBP) with the Coagulation Factor VIII." Thrombosis Research 102, no. 2 (April 2001): 177–85. http://dx.doi.org/10.1016/s0049-3848(01)00229-8.

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Farrar, Christopher S., Geoffrey T. Rouin, Benjamin L. Miller, Carol H. Raeman, Nancie A. Mooney, and Denise C. Hocking. "A Matricryptic Conformation of the Integrin-Binding Domain of Fibronectin Regulates Platelet-Derived Growth Factor-Induced Intracellular Calcium Release." Cells 8, no. 11 (October 30, 2019): 1351. http://dx.doi.org/10.3390/cells8111351.

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Platelet-derived growth factor (PDGF) signaling is dysregulated in a wide variety of diseases, making PDGF an attractive therapeutic target. However, PDGF also affects numerous signaling cascades essential for tissue homeostasis, limiting the development of PDGF-based therapies that lack adverse side-effects. Recent studies showed that fibroblast-mediated assembly of extracellular matrix (ECM) fibronectin fibrils attenuates PDGF-induced intracellular calcium release by selectively inhibiting phosphoinositol 3-kinase (PI3K) activation while leaving other PDGF-mediated signaling cascades intact. In the present study, a series of recombinant fibronectin-derived fusion proteins were used to localize the sequences in fibronectin that are responsible for this inhibition. Results demonstrate that attenuation of PDGF-induced intracellular calcium release by the fibronectin matrix mimetic, FNIII1H,8-10 requires α5β1 integrin ligation, but is not dependent upon the matricryptic, heparin-binding site of FNIII1. Intact cell-binding fibronectin fragments were also unable to attenuate PDGF-induced intracellular calcium release. In contrast, a novel integrin-binding fragment that adopts an extended and aligned conformational state, inhibited both PI3K activation and intracellular calcium release in response to PDGF. Taken together, these studies provide evidence that attenuation of PDGF-induced intracellular calcium release by fibronectin is mediated by a novel conformation of the α5β1 integrin-binding, FNIII9-10 modules, that is expressed by fibrillar fibronectin.

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Zhang, Ming-Ming, Ling-Ling Luo, Yu Liu, Gui-Jie Wang, Huan-Huan Zheng, Xu-Sheng Liu, and Jia-Lin Wang. "Calcium and integrin-binding protein 1-like interacting with an integrin α-cytoplasmic domain facilitates cellular immunity in Helicoverpa armigera." Developmental & Comparative Immunology 131 (June 2022): 104379. http://dx.doi.org/10.1016/j.dci.2022.104379.

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Yamniuk, Aaron P., Jessica L. Gifford, Sara Linse, and Hans J. Vogel. "Effects of Metal-Binding Loop Mutations on Ligand Binding to Calcium- and Integrin-Binding Protein 1. Evolution of the EF-Hand?†." Biochemistry 47, no. 6 (February 2008): 1696–707. http://dx.doi.org/10.1021/bi701494m.

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Wu, Xin, Jon E. Mogford, Steven H. Platts, George E. Davis, Gerald A. Meininger, and Michael J. Davis. "Modulation of Calcium Current in Arteriolar Smooth Muscle by αvβ3 and α5β1 Integrin Ligands." Journal of Cell Biology 143, no. 1 (October 5, 1998): 241–52. http://dx.doi.org/10.1083/jcb.143.1.241.

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Vasoactive effects of soluble matrix proteins and integrin-binding peptides on arterioles are mediated by αvβ3 and α5β1 integrins. To examine the underlying mechanisms, we measured L-type Ca2+ channel current in arteriolar smooth muscle cells in response to integrin ligands. Whole-cell, inward Ba2+ currents were inhibited after application of soluble cyclic RGD peptide, vitronectin (VN), fibronectin (FN), either of two anti–β3 integrin antibodies, or monovalent β3 antibody. With VN or β3 antibody coated onto microbeads and presented as an insoluble ligand, current was also inhibited. In contrast, beads coated with FN or α5 antibody produced significant enhancement of current after bead attachment. Soluble α5 antibody had no effect on current but blocked the increase in current evoked by FN-coated beads and enhanced current when applied in combination with an appropriate IgG. The data suggest that αvβ3 and α5β1 integrins are differentially linked through intracellular signaling pathways to the L-type Ca2+ channel and thereby alter control of Ca2+ influx in vascular smooth muscle. This would account for the vasoactive effects of integrin ligands on arterioles and provide a potential mechanism for wound recognition during tissue injury.

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Pacifici, R., J. Roman, R. Kimble, R. Civitelli, C. M. Brownfield, and C. Bizzarri. "Ligand binding to monocyte alpha 5 beta 1 integrin activates the alpha 2 beta 1 receptor via the alpha 5 subunit cytoplasmic domain and protein kinase C." Journal of Immunology 153, no. 5 (September 1, 1994): 2222–33. http://dx.doi.org/10.4049/jimmunol.153.5.2222.

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Abstract Regulation of the functional status of integrin receptors plays a critical role in inflammation and tissue remodeling, as it affects cell adherence and cytokine secretion. We have previously shown that in monocytes the binding of collagen to the alpha 2 beta 1 integrin induces the release of IL-1, an event that is potentiated by binding of fibronectin (Fn) to the alpha 5 beta 1 integrin. In this study, we have investigated the mechanisms leading to this phenomenon. Fn binding to alpha 5 beta 1 induced intracellular signals which increased the alpha 2 beta 1-dependent adhesiveness of monocytes to collagen without modifications of alpha 2 beta 1 expression. By using Abs against the intracellular region of the alpha 5 subunit of the alpha 5 beta 1 receptor, and specific inhibitors of protein kinase C (PKC), we found that the potentiation effect of Fn on monocyte IL-1 production and their adherence to collagen was dependent on an intact alpha 5 subunit cytoplasmic domain, and required PKC activation. Although the alpha 2 beta 1 could be activated by several intracellular second messengers, including protein kinase A and intracellular calcium, the potentiating effect of Fn was mediated only by PKC. These data provide an example of a novel regulatory mechanism: potentiation of beta 1 integrin-mediated events as a result of ligand binding to another integrin of the same class. They also show that the intracellular region of alpha 5 beta 1 plays a critical role in transducing signals generated by ligand binding to alpha 5 beta 1.

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Rabinowich, H., W. C. Lin, R. B. Herberman, and T. L. Whiteside. "Signaling via CD7 molecules on human NK cells. Induction of tyrosine phosphorylation and beta 1 integrin-mediated adhesion to fibronectin." Journal of Immunology 153, no. 8 (October 15, 1994): 3504–13. http://dx.doi.org/10.4049/jimmunol.153.8.3504.

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Abstract We have previously reported that CD7 expressed on resting human NK cells is a signal-transducing molecule, which upon ligation with mAb induces a rapid increase in cytoplasmic free calcium, secretion of IFN-gamma, and augmented NK activity against K562 targets. We now demonstrate that Ab-mediated clustering of CD7 molecules on NK cells results in enhanced phosphorylation on tyrosine residues of intracellular proteins of 60, 70, 80, 97, and 120 kDa. In the presence of genistein, a specific inhibitor of protein tyrosine kinase, the enhanced level of tyrosine phosphorylation was blocked, indicating that CD7 may induce signaling via activation of tyrosine kinases. Cross-linking of CD7 or CD16 molecules with primary and secondary Abs, as well as stimulation of NK cells with phorbol ester (PMA) or with calcium ionophore A23187 also induced beta 1 integrin-mediated adhesion of these cells to fibronectin (FN)-coated plastic surfaces. In contrast, cross-linking of CD2 expressed on the surface of NK cells had no significant effect on NK cell adhesion to FN. This adhesion was not associated with up-regulation of expression of alpha 4 beta 1 or alpha 5 beta 1 FN receptors on NK cells, but it required an intact cytoskeleton. The CD7-induced adhesion to FN was mediated by alpha 4 beta 1 and alpha 5 beta 1 integrins, as it was partially blocked by FN connective segment-1 peptide (EILDVPST), the alpha 4 beta 1-binding domain, as well as by RGD-containing peptides, the alpha 5 beta 1-binding domain, but not by EILEVPST or RGE control peptides. NK cell binding to FN was also partially inhibited by mAb to alpha 4, alpha 5, and beta 1 integrins. The mechanism by which cross-linking of CD7 or CD16 on NK cells induced adhesion to FN appeared to involve both protein tyrosine kinase and protein kinase C, because this adhesion was blocked in the presence of either genistein or a protein kinase C inhibitor, staurosporin. Our data demonstrate that signals transduced via triggering of either CD7 or CD16 molecules are involved in the regulation of the functional activity of beta 1 integrins on NK cells.

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Heemskerk, Johan. "Regulation of Platelet Procoagulant Activity." Blood 126, no. 23 (December 3, 2015): SCI—33—SCI—33. http://dx.doi.org/10.1182/blood.v126.23.sci-33.sci-33.

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Abstract Platelets play prominent and unique roles in the kinetics of the coagulation process. Modulated by the flow conditions, they control coagulation in various ways: (1) by integrin activation and ensuing clot retraction; (2) via exposure of the procoagulant phospholipid phosphatidylserine (PS), which causes binding of a specific set of coagulation factors at the platelet surface with as a result tenase activation and thrombin generation; (3) by initiating fibrin fiber formation at the platelet surface, a process specifically catalyzed by coated platelets. Recent evidence points to fibrin as an active structural network, which provides binding sides for plasma factors and platelets and, thereby, provides an important feedback mechanism for the stimulation of platelet activation. This overview will focus on novel insights into the signaling and activation processes in platelets that regulate these distinct procoagulant functions. One key mechanism is the activation and secondary closure of integrin alphaIIb-beta3. Another key mechanism concerns the calcium-dependent exposure of PS, which is accompanied by swelling of the platelets. Together, these processes control not only platelet adhesion, but also the accessibility for coagulation factors. Major distortions in these procoagulant functions are seen in platelets from a patient with the Scott syndrome, a rare bleeding disorder associated with mutations in the calcium-dependent ion channel protein anoctamin-6 (gene ANO6, previously TMEM16A). These platelets are deficient in calcium-induced PS exposure, swelling, integrin inactivation and in the formation of thrombin and fibrin at the platelet surface. These dysfunctions are precisely phenocopied in mice lacking anoctamin-6 expression. Advanced platelet proteomics analysis indicated that the deficiency in anoctamin-6 was accompanied by decreased calpain-dependent cleavage of a whole spectrum of intracellular proteins, and an increased phosphorylation state of many signaling and cytoskeletal proteins. However, calcium signaling in the Scott platelets was unchanged. In contrast, reports on patients with a gain in platelet procoagulant function, the Stormorken syndrome, indicate a link with genetic mutation in the calcium signaling protein STIM1. The possible consequences of these novel insights for our understanding of haemorrhagic and thrombotic deseases will be discussed. Disclosures No relevant conflicts of interest to declare.

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Morris, Kenise, and Anne-Laure Papa. "Abstract A004: The role of calcium in metastatic progression." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): A004. http://dx.doi.org/10.1158/1538-7445.metastasis22-a004.

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Abstract Calcium is essential to the structural stability of integrin proteins implicated in platelet–cancer cell interactions, namely integrins GPIIb/IIIa and avb3, which share a common beta subunit (Pelletier et al., J Biol Chem, 1996), (Zhang and Chen, Cell Adh Migr, 2012). Additionally, calcium is essential for ligand binding to these integrins (e.g., fibrinogen) that bridge platelets and cancer cells (Raborn et al., Biochemistry, 2011) and for the downstream signaling following mechanical and chemical stimulation in the integrin microenvironment (Michelson, Platelets, 2013). Platelet-cancer cell interactions are key players in cancer progression as platelets support metastatic dissemination (Morris et al., Biochim. Biophys. Acta BBA - Rev. Cancer, 2022). Despite previous studies recognizing calcium’s role in integrin stability and function, calcium’s importance for platelet support in cancer progression is not well understood. Therefore, we aim to (1) characterize the receptor expression and ligand binding ability of GPIIb/IIIa and avb3 on respective cells via anti-CD41a (for platelets and breast cancer MDA-MB-231 cells) and anti-avb3 antibody (for lung cancer A549 cells), (2) characterize platelet function by assessing platelet aggregation using light transmission aggregometry and platelet adhesion on a thrombogenic surface, (3) characterize platelet-cancer cell interaction via flow cytometry, and (4) assess cancer cell invasion in the presence of platelets via transwell assay; all in the presence of an environment with calcium chelation and hypercalcemic conditions. Our results demonstrate that platelet GPIIb/IIIa, cancer cell GPIIb/IIIa (MDA-MB-231) and cancer cell integrin avb3 (A549) are modulated with calcium chelation. Additionally, platelet function, specifically aggregation is significantly decreased with calcium chelation and significantly increased with hypercalcemia. We also observed that the interaction between platelets and cancer cells is reduced with calcium chelation, platelet-MDA-MB-231 interaction specifically being significantly reduced in the presence of sodium citrate. Our overall hypothesis is that the observed effect of calcium levels of platelet and cancer cell integrins could have a significant influence on platelet-cancer cell interactions and cancer cell migration in hypercalcemia, often seen in patients with malignancy. A greater understanding of these interactions could have impact for the design of specific inhibitors with anti-metastatic effects and potentially lead to novel targeted therapies to combat metastatic dissemination. Citation Format: Kenise Morris, Anne-Laure Papa. The role of calcium in metastatic progression [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A004.

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Huang, Jingnan, Natalie J. Jooss, Delia I. Fernández, Albert Sickmann, Ángel García, Kanin Wichapong, Ingrid Dijkgraaf, and Johan W. M. Heemskerk. "Roles of Focal Adhesion Kinase PTK2 and Integrin αIIbβ3 Signaling in Collagen- and GPVI-Dependent Thrombus Formation under Shear." International Journal of Molecular Sciences 23, no. 15 (August 4, 2022): 8688. http://dx.doi.org/10.3390/ijms23158688.

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Glycoprotein (GP)VI and integrin αIIbβ3 are key signaling receptors in collagen-dependent platelet aggregation and in arterial thrombus formation under shear. The multiple downstream signaling pathways are still poorly understood. Here, we focused on disclosing the integrin-dependent roles of focal adhesion kinase (protein tyrosine kinase 2, PTK2), the shear-dependent collagen receptor GPR56 (ADGRG1 gene), and calcium and integrin-binding protein 1 (CIB1). We designed and synthetized peptides that interfered with integrin αIIb binding (pCIB and pCIBm) or mimicked the activation of GPR56 (pGRP). The results show that the combination of pGRP with PTK2 inhibition or of pGRP with pCIB > pCIBm in additive ways suppressed collagen- and GPVI-dependent platelet activation, thrombus buildup, and contraction. Microscopic thrombus formation was assessed by eight parameters (with script descriptions enclosed). The suppressive rather than activating effects of pGRP were confined to blood flow at a high shear rate. Blockage of PTK2 or interference of CIB1 no more than slightly affected thrombus formation at a low shear rate. Peptides did not influence GPVI-induced aggregation and Ca2+ signaling in the absence of shear. Together, these data reveal a shear-dependent signaling axis of PTK2, integrin αIIbβ3, and CIB1 in collagen- and GPVI-dependent thrombus formation, which is modulated by GPR56 and exclusively at high shear. This work thereby supports the role of PTK2 in integrin αIIbβ3 activation and signaling.

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Naik, Meghna U., and Ulhas P. Naik. "Calcium-and integrin-binding protein regulates focal adhesion kinase activity during platelet spreading on immobilized fibrinogen." Blood 102, no. 10 (November 15, 2003): 3629–36. http://dx.doi.org/10.1182/blood-2003-05-1703.

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AbstractPlatelet spreading on the subendothelium in response to vascular injury is fundamental to the regulation of physiologic hemostasis. Previously, we have shown that, when bound to glycoprotein IIb (GPIIb), calcium- and integrin-binding protein (CIB) regulates platelet spreading on immobilized fibrinogen (Fg). In this study, we investigated the signaling events that occur downstream of CIB in the absence of signaling that occurs as a result of granular secretion. Using Chinese hamster ovary (CHO) cells as a model, we demonstrate that CIB induces cell migration. Immunofluorescence analysis of CIB localization indicates that endogenous CIB accumulates in areas of focal adhesions, and its overexpression up-regulates the formation of focal adhesion complexes compared with control cells. Immunoprecipitation analysis indicates that CIB associates with focal adhesion kinase (FAK), a key regulator in focal complex formation, and up-regulates its activity. Overexpression of dominant-negative FAK, FRNK, along with CIB in CHO cells completely inhibits CIB-induced cell migration. Further, confirmation of these data in the platelet system indicates that CIB and FAK associate throughout all stages of platelet spreading but only on Fg binding to GPIIb/IIIa. Taken together, our results suggest that CIB regulates platelet spreading through the regulation of FAK activation. (Blood. 2003;102: 3629-3636)

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Sun, Wei, Qun Guan, Ji Wen, Qiyao Zhang, Weina Yang, Bin Zhang, Wei Cui, Zhiquan Zou, and Yan Yu. "Calcium- and integrin-binding protein-1 is down-regulated in the sperm of patients with oligoasthenozoospermia." Journal of Assisted Reproduction and Genetics 31, no. 5 (January 26, 2014): 541–47. http://dx.doi.org/10.1007/s10815-014-0177-4.

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45

Muza-Moons, Michelle M., Athanasia Koutsouris, and Gail Hecht. "Disruptionof Cell Polarity by Enteropathogenic Escherichia coli EnablesBasolateral Membrane Proteins To Migrate Apically and ToPotentiate PhysiologicalConsequences." Infection and Immunity 71, no. 12 (December 2003): 7069–78. http://dx.doi.org/10.1128/iai.71.12.7069-7078.2003.

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ABSTRACT Enteropathogenic Escherichia coli (EPEC) disrupts the structure and barrier function of host intestinal epithelial tight junctions (TJs). The impact of EPEC on TJ “fence function,” i.e., maintenance of cell polarity, has not been investigated. In polarized cells, proteins such as β1-integrin and Na+/K+ ATPase are restricted to basolateral (BL) membranes. The outer membrane EPEC protein intimin possesses binding sites for the EPEC translocated intimin receptor (Tir) and β1-integrin. Restriction ofβ 1-integrin to BL domains, however, precludes opportunity for interaction. We hypothesize that EPEC perturbs TJ fence function and frees BL proteins such as β1-integrin to migrate to apical (AP) membranes of host cells, thus allowing interactions with bacterial adhesins such as intimin. The aim of this study was to determine whether EPEC alters the polar distribution of BL proteins, in particular β1-integrin, and if such redistribution contributes to pathogenesis. Human intestinal epithelial T84 cells and EPEC strain E2348/69 were used. Selective biotinylation of AP or BL membrane proteins and confocal microscopy showed the presence of β1-integrin and Na+/K+ ATPase on the AP membrane following infection. β1-Integrin antibody afforded no protection against the initial EPEC-induced decrease in transepithelial electrical resistance (TER) but halted the progressive decrease at later time points. While the effects of EPEC on TJ barrier and fence function were Tir dependent, disruption of cell polarity by calcium chelation allowed a tir mutant to be nearly as effective as wild-type EPEC. In contrast, deletion of espD, which renders the type III secretory system ineffective, had no effect on TER even after calcium chelation, suggesting that the putativeβ 1-integrin-intimin interaction serves to provide intimate contact, like that of Tir and intimin, making translocation of effector molecules more efficient. We conclude that the initial alterations of TJ barrier and fence function by EPEC are Tir dependent but that later disruption of cell polarity and accessibility of EPEC to BL membrane proteins, such asβ 1-integrin, potentiates the physiological perturbations.

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Hwang, P. M., and H. J. Vogel. "Structures of the platelet calcium- and integrin-binding protein and the ?IIb-integrin cytoplasmic domain suggest a mechanism for calcium-regulated recognition; homology modelling and NMR studies." Journal of Molecular Recognition 13, no. 2 (March 2000): 83–92. http://dx.doi.org/10.1002/(sici)1099-1352(200003/04)13:2<83::aid-jmr491>3.0.co;2-a.

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47

Yamniuk, Aaron P., Hiroaki Ishida, and Hans J. Vogel. "The Interaction between Calcium- and Integrin-binding Protein 1 and the αIIb Integrin Cytoplasmic Domain Involves a Novel C-terminal Displacement Mechanism." Journal of Biological Chemistry 281, no. 36 (July 6, 2006): 26455–64. http://dx.doi.org/10.1074/jbc.m603963200.

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Tucker, Katherine L., Joanne M. Stevens, Peter A. Jordan, Tanya Sage, Sarah Jones, Natasha E. Barrett, Rene St-Arnaud, Jonathan Frampton, Shoukat Dedhar, and Jonathan M. Gibbins. "Integrin Linked Kinase Is Important in Platelet Signalling and Function." Blood 110, no. 11 (November 16, 2007): 420. http://dx.doi.org/10.1182/blood.v110.11.420.420.

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Abstract Integrin linked kinase (ILK) is a 59 kDa protein that has been previously implicated in both collagen- and thrombin-induced platelet activation. Platelet stimulation results in the transient activation of ILK kinase activity and movement to the plasma membrane where signaling complexes are formed with beta 1 and beta 3 integrins. The change in ILK activity and association with beta 1 and beta 3 integrins that occurs upon stimulation suggests that this protein may be important for the co-ordination of platelet responses. We have successfully developed a conditional ILK knockout mouse model using the Cre-Lox system to enable the study of platelets deficient in this protein. ILK deficient mice appear healthy and have normal platelet levels by day 8 following induction of gene deletion. ILK deficient platelets display reduced aggregation and fibrinogen binding in response to agonists such as collagen and thrombin. This is accompanied by a secretion defect, although early collagen stimulated signaling such as PLCγ2 phosphorylation and calcium mobilization are unaffected. Analysis of blood from ILK deficient mice using an in vitro flow system showed reduced thrombus formation under arterial conditions. Furthermore, extended bleeding times were observed in these mice. The data presented here demonstrates that ILK has a role in platelet regulation and is important for functional haemostasis.

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Huang, MM, L. Lipfert, M. Cunningham, JS Brugge, MH Ginsberg, and SJ Shattil. "Adhesive ligand binding to integrin alpha IIb beta 3 stimulates tyrosine phosphorylation of novel protein substrates before phosphorylation of pp125FAK." Journal of Cell Biology 122, no. 2 (July 15, 1993): 473–83. http://dx.doi.org/10.1083/jcb.122.2.473.

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Tyrosine phosphorylation of multiple platelet proteins is stimulated by thrombin and other agonists that cause platelet aggregation and secretion. The phosphorylation of a subset of these proteins, including a protein tyrosine kinase, pp125FAK, is dependent on the platelet aggregation that follows fibrinogen binding to integrin alpha IIb beta 3. In this report, we examined whether fibrinogen binding, per se, triggers a process of tyrosine phosphorylation in the absence of exogenous agonists. Binding of soluble fibrinogen was induced with Fab fragments of an anti-beta 3 antibody (anti-LIBS6) that directly exposes the fibrinogen binding site in alpha IIb beta3. Proteins of 50-68 KD and 140 kD became phosphorylated on tyrosine residues in a fibrinogen-dependent manner. This response did not require prostaglandin synthesis, an increase in cytosolic free calcium, platelet aggregation or granule secretion, nor was it associated with tyrosine phosphorylation of pp125FAK. Tyrosine phosphorylation of the 50-68-kD and 140-kD proteins was also observed when (a) fibrinogen binding was stimulated by agonists such as epinephrine, ADP, or thrombin instead of by anti-LIBS6; (b) fragment X, a dimeric plasmin-derived fragment of fibrinogen was used instead of fibrinogen; or (c) alpha IIb beta 3 complexes were cross-linked by antibodies, even in the absence of fibrinogen. In contrast, no tyrosine phosphorylation was observed when the ligand consisted of monomeric cell recognition peptides derived from fibrinogen (RGDS or gamma 400-411). Fibrinogen-dependent tyrosine phosphorylation was inhibited by cytochalasin D. These studies demonstrate that fibrinogen binding to alpha IIb beta 3 initiates a process of tyrosine phosphorylation that precedes platelet aggregation and the phosphorylation of pp125FAK. This reaction may depend on the oligomerization of integrin receptors and on the state of actin polymerization, organizational processes that may juxtapose tyrosine kinases with their substrates.

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Loewen, Matthew E., and George W. Forsyth. "Structure and Function of CLCA Proteins." Physiological Reviews 85, no. 3 (July 2005): 1061–92. http://dx.doi.org/10.1152/physrev.00016.2004.

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CLCA proteins were discovered in bovine trachea and named for a calcium-dependent chloride conductance found in trachea and in other secretory epithelial tissues. At least four closely located gene loci in the mouse and the human code for independent isoforms of CLCA proteins. Full-length CLCA proteins have an unprocessed mass ratio of ∼100 kDa. Three of the four human loci code for the synthesis of membrane-associated proteins. CLCA proteins affect chloride conductance, epithelial secretion, cell-cell adhesion, apoptosis, cell cycle control, mucus production in asthma, and blood pressure. There is a structural and probable functional divergence between CLCA isoforms containing or not containing β4-integrin binding domains. Cell cycle control and tumor metastasis are affected by isoforms with the binding domains. These isoforms are expressed prominently in smooth muscle, in some endothelial cells, in the central nervous system, and also in secretory epithelial cells. The isoform with disrupted β4-integrin binding (hCLCA1, pCLCA1, mCLCA3) alters epithelial mucus secretion and ion transport processes. It is preferentially expressed in secretory epithelial tissues including trachea and small intestine. Chloride conductance is affected by the expression of several CLCA proteins. However, the dependence of the resulting electrical signature on the expression system rather than the CLCA protein suggests that these proteins are not independent Ca2+-dependent chloride channels, but may contribute to the activity of chloride channels formed by, or in conjunction with, other proteins.

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Journal articles on the topic 'Calcium and integrin binding protein'

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