Journal articles: 'Tbc1D3'

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Frittoli, Emanuela, Andrea Palamidessi, Alessandro Pizzigoni, Letizia Lanzetti, Massimiliano Garrè, Flavia Troglio, Albino Troilo, et al. "The Primate-specific Protein TBC1D3 Is Required for Optimal Macropinocytosis in a Novel ARF6-dependent Pathway." Molecular Biology of the Cell 19, no. 4 (April 2008): 1304–16. http://dx.doi.org/10.1091/mbc.e07-06-0594.

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The generation of novel genes and proteins throughout evolution has been proposed to occur as a result of whole genome and gene duplications, exon shuffling, and retrotransposition events. The analysis of such genes might thus shed light into the functional complexity associated with highly evolved species. One such case is represented by TBC1D3, a primate-specific gene, harboring a TBC domain. Because TBC domains encode Rab-specific GAP activities, TBC-containing proteins are predicted to play a major role in endocytosis and intracellular traffic. Here, we show that the TBC1D3 gene originated late in evolution, likely through a duplication of the RNTRE locus, and underwent gene amplification during primate speciation. Despite possessing a TBC domain, TBC1D3 is apparently devoid of Rab-GAP activity. However, TBC1D3 regulates the optimal rate of epidermal growth factor–mediated macropinocytosis by participating in a novel pathway involving ARF6 and RAB5. In addition, TBC1D3 binds and colocalize to GGA3, an ARF6-effector, in an ARF6-dependent manner, and synergize with it in promoting macropinocytosis, suggesting that the two proteins act together in this process. Accordingly, GGA3 siRNA-mediated ablation impaired TBC1D3-induced macropinocytosis. We thus uncover a novel signaling pathway that appeared after primate speciation. Within this pathway, a TBC1D3:GGA3 complex contributes to optimal propagation of signals, ultimately facilitating the macropinocytic process.

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Tobias, Irene S., Kara K. Lazauskas, Jeremy Siu, Pablo B. Costa, Jared W. Coburn, and Andrew J. Galpin. "Sex and fiber type independently influence AMPK, TBC1D1, and TBC1D4 at rest and during recovery from high-intensity exercise in humans." Journal of Applied Physiology 128, no. 2 (February 1, 2020): 350–61. http://dx.doi.org/10.1152/japplphysiol.00704.2019.

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Women and men present different metabolic responses to exercise, yet whether this phenomenon results from differences in fiber type (FT) composition or other sex-specific factors remains unclear. Therefore, our aim was to examine the effects of sex and FT independently on AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), Tre-2/BUB2/CDC1 domain family (TBC1D)1, and TBC1D4 in response to acute exercise. Segregated pools of myosin heavy chain (MHC) I and MHC IIa fibers were prepared from vastus lateralis biopsies of young trained men and women at rest and during recovery (0 min, 45 min, 90 min, or 180 min) from high-intensity interval exercise (6 × 1.5 min at 95% maximum oxygen uptake). In resting MHC I vs. IIa fibers, AMPKα2, AMPKγ3, and TBC1D1 were higher and TBC1D4 expression was lower in both sexes, along with higher phospho (p)-TBC1D1Ser660 and lower p-TBC1D4Thr642. Women expressed higher ACC than men in MHC IIa fibers and higher AMPKβ1, AMPKβ2, TBC1D1, and TBC1D4 in both FTs. Immediately after exercise, p-AMPKαThr172 increased only in MHC IIa fibers, whereas p-ACCSer221 increased in both FTs, with no change in p-TBC1D1Ser660 or p-TBC1D4Thr642. During recovery, delayed responses were observed for p-AMPKαThr172 in MHC I (45 min), p-TBC1D4Thr642 in both FTs (45 min), and p-TBC1D1Ser660 (180 min). FT-specific phosphorylation responses to exercise were similar between men and women. Data indicate that sex and FT independently influence expression of AMPK and its substrates. Thus failing to account for sex or FT may reduce accuracy and precision of metabolic protein measurements and conceal key findings. NEW & NOTEWORTHY This investigation is the first to compare muscle fiber type (FT)-specific analysis of proteins between the sexes, providing comprehensive data on AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), Tre-2/BUB2/CDC1 domain family (TBC1D)1, and TBC1D4 before and in the hours following high-intensity interval exercise (HIIT). Expression and phosphorylation of specific AMPK isoforms, ACC, TBC1D1, and TBC1D4 were shown to be FT dependent, sex dependent, or both, and TBC1D1 showed an unexpected delay in FT-dependent phosphorylation in the time period following HIIT.

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Penisson, Maxime, Mingyue Jin, Shengming Wang, Shinji Hirotsune, Fiona Francis, and Richard Belvindrah. "Lis1 mutation prevents basal radial glia-like cell production in the mouse." Human Molecular Genetics 31, no. 6 (October 12, 2021): 942–57. http://dx.doi.org/10.1093/hmg/ddab295.

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Abstract Human cerebral cortical malformations are associated with progenitor proliferation and neuronal migration abnormalities. Progenitor cells include apical radial glia, intermediate progenitors and basal (or outer) radial glia (bRGs or oRGs). bRGs are few in number in lissencephalic species (e.g. the mouse) but abundant in gyrencephalic brains. The LIS1 gene coding for a dynein regulator, is mutated in human lissencephaly, associated also in some cases with microcephaly. LIS1 was shown to be important during cell division and neuronal migration. Here, we generated bRG-like cells in the mouse embryonic brain, investigating the role of Lis1 in their formation. This was achieved by in utero electroporation of a hominoid-specific gene TBC1D3 (coding for a RAB-GAP protein) at mouse embryonic day (E) 14.5. We first confirmed that TBC1D3 expression in wild-type (WT) brain generates numerous Pax6+ bRG-like cells that are basally localized. Second, using the same approach, we assessed the formation of these cells in heterozygote Lis1 mutant brains. Our novel results show that Lis1 depletion in the forebrain from E9.5 prevented subsequent TBC1D3-induced bRG-like cell amplification. Indeed, we observe perturbation of the ventricular zone (VZ) in the mutant. Lis1 depletion altered adhesion proteins and mitotic spindle orientations at the ventricular surface and increased the proportion of abventricular mitoses. Progenitor outcome could not be further altered by TBC1D3. We conclude that disruption of Lis1/LIS1 dosage is likely to be detrimental for appropriate progenitor number and position, contributing to lissencephaly pathogenesis.

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Espelage, Lena, Hadi Al-Hasani, and Alexandra Chadt. "RabGAPs in skeletal muscle function and exercise." Journal of Molecular Endocrinology 64, no. 1 (January 2020): R1—R19. http://dx.doi.org/10.1530/jme-19-0143.

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The two closely related RabGAPs TBC1D1 and TBC1D4 are key signaling factors of skeletal muscle substrate utilization. In mice, deficiency in both RabGAPs leads to reduced skeletal muscle glucose transport in response to insulin and lower GLUT4 abundance. Conversely, Tbc1d1 and Tbc1d4 deficiency results in enhanced lipid use as fuel in skeletal muscle, through yet unknown mechanisms. In humans, variants in TBC1D1 and TBC1D4 are linked to obesity, insulin resistance and type 2 diabetes. While the specific function in metabolism of each of the two RabGAPs remains to be determined, TBC1D1 emerges to be controlling exercise endurance and physical capacity, whereas TBC1D4 may rather be responsible for maintaining muscle insulin sensitivity, muscle contraction, and exercise. There is growing evidence that TBC1D1 also plays an important role in skeletal muscle development, since it has been found to be associated to meat production traits in several livestock species. In addition, TBC1D1 protein abundance in skeletal muscle is regulated by both, insulin receptor and insulin-like growth factor-1 (IGF-1) receptor signaling. This review focuses on the specific roles of the two key signaling factors TBC1D1 and TBC1D4 in skeletal muscle metabolism, development and exercise physiology.

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Mikłosz, Agnieszka, Bartłomiej Łukaszuk, Elżbieta Supruniuk, Kamil Grubczak, Marcin Moniuszko, Barbara Choromańska, Piotr Myśliwiec, and Adrian Chabowski. "Does TBC1D4 (AS160) or TBC1D1 Deficiency Affect the Expression of Fatty Acid Handling Proteins in the Adipocytes Differentiated from Human Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Obtained from Subcutaneous and Visceral Fat Depots?" Cells 10, no. 6 (June 16, 2021): 1515. http://dx.doi.org/10.3390/cells10061515.

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TBC1D4 (AS160) and TBC1D1 are Rab GTPase-activating proteins that play a key role in the regulation of glucose and possibly the transport of long chain fatty acids (LCFAs) into muscle and fat cells. Knockdown (KD) of TBC1D4 increased CD36/SR-B2 and FABPpm protein expressions in L6 myotubes, whereas in murine cardiomyocytes, TBC1D4 deficiency led to a redistribution of CD36/SR-B2 to the sarcolemma. In our study, we investigated the previously unexplored role of both Rab-GAPs in LCFAs uptake in human adipocytes differentiated from the ADMSCs of subcutaneous and visceral adipose tissue origin. To this end we performed a single- and double-knockdown of the proteins (TBC1D1 and TBC1D4). Herein, we provide evidence that AS160 mediates fatty acid entry into the adipocytes derived from ADMSCs. TBC1D4 KD resulted in quite a few alterations to the cellular phenotype, the most obvious of which was the shift of the CD36/SR-B2 transport protein to the plasma membrane. The above translated into an increased uptake of saturated long-chain fatty acid. Interestingly, we observed a tissue-specific pattern, with more pronounced changes present in the adipocytes derived from subADMSCs. Altogether, our data show that in human adipocytes, TBC1D4, but not TBC1D1, deficiency increases LCFAs transport via CD36/SR-B2 translocation.

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Zhou, Qiong L., Zhen Y. Jiang, John Holik, Anil Chawla, G. Nana Hagan, John Leszyk, and Michael P. Czech. "Akt substrate TBC1D1 regulates GLUT1 expression through the mTOR pathway in 3T3-L1 adipocytes." Biochemical Journal 411, no. 3 (April 14, 2008): 647–55. http://dx.doi.org/10.1042/bj20071084.

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Multiple studies have suggested that the protein kinase Akt/PKB (protein kinase B) is required for insulin-stimulated glucose transport in skeletal muscle and adipose cells. In an attempt to understand links between Akt activation and glucose transport regulation, we applied mass spectrometry-based proteomics and bioinformatics approaches to identify potential Akt substrates containing the phospho-Akt substrate motif RXRXXpS/T. The present study describes the identification of the Rab GAP (GTPase-activating protein)-domain containing protein TBC1D1 [TBC (Tre-2/Bub2/Cdc16) domain family, member 1], which is closely related to TBC1D4 [TBC domain family, member 4, also denoted AS160 (Akt substrate of 160 kDa)], as an Akt substrate that is phosphorylated at Thr590. RNAi (RNA interference)-mediated silencing of TBC1D1 elevated basal deoxyglucose uptake by approx. 61% in 3T3-L1 mouse embryo adipocytes, while the suppression of TBC1D4 and RapGAP220 under the same conditions had little effect on basal and insulin-stimulated deoxyglucose uptake. Silencing of TBC1D1 strongly increased expression of the GLUT1 glucose transporter but not GLUT4 in cultured adipocytes, whereas the decrease in TBC1D4 had no effect. Remarkably, loss of TBC1D1 in 3T3-L1 adipocytes activated the mTOR (mammalian target of rapamycin)-p70 S6 protein kinase pathway, and the increase in GLUT1 expression in the cells treated with TBC1D1 siRNA (small interfering RNA) was blocked by the mTOR inhibitor rapamycin. Furthermore, overexpression of the mutant TBC1D1-T590A, lacking the putative Akt/PKB phosphorylation site, inhibited insulin stimulation of p70 S6 kinase phosphorylation at Thr389, a phosphorylation induced by mTOR. Taken together, our data suggest that TBC1D1 may be involved in controlling GLUT1 glucose transporter expression through the mTOR-p70 S6 kinase pathway.

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Mafakheri, Samaneh, Alexandra Chadt, and Hadi Al-Hasani. "Regulation of RabGAPs involved in insulin action." Biochemical Society Transactions 46, no. 3 (May 21, 2018): 683–90. http://dx.doi.org/10.1042/bst20170479.

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Rab (Ras-related proteins in brain) GTPases are key proteins responsible for a multiplicity of cellular trafficking processes. Belonging to the family of monomeric GTPases, they are regulated by cycling between their active GTP-bound and inactive GDP-bound conformations. Despite possessing a slow intrinsic GTP hydrolysis activity, Rab proteins rely on RabGAPs (Rab GTPase-activating proteins) that catalyze GTP hydrolysis and consequently inactivate the respective Rab GTPases. Two related RabGAPs, TBC1D1 and TBC1D4 (=AS160) have been described to be associated with obesity-related traits and type 2 diabetes in both mice and humans. Inactivating mutations of TBC1D1 and TBC1D4 lead to substantial changes in trafficking and subcellular distribution of the insulin-responsive glucose transporter GLUT4, and to subsequent alterations in energy substrate metabolism. The activity of the RabGAPs is controlled through complex phosphorylation events mediated by protein kinases including AKT and AMPK, and by putative regulatory interaction partners. However, the dynamics and downstream events following phosphorylation are not well understood. This review focuses on the specific role and regulation of TBC1D1 and TBC1D4 in insulin action.

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Qin, Shu, Robert A. Dorschner, Irene Masini, Ophelia Lavoie‐Gagne, Philip D. Stahl, Todd W. Costantini, Andrew Baird, and Brian P. Eliceiri. "TBC1D3 regulates the payload and biological activity of extracellular vesicles that mediate tissue repair." FASEB Journal 33, no. 5 (February 4, 2019): 6129–39. http://dx.doi.org/10.1096/fj.201802388r.

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Shen, Y., L. Zhang, H. Zhao, and C. L. Shen. "TC-1 mediate the TBC1D3 oncogene induced migration of MCF-7 breast cancer cells." Annals of Oncology 29 (November 2018): ix19. http://dx.doi.org/10.1093/annonc/mdy428.017.

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Kong, Chen, Jeffrey J. Lange, Dmitri Samovski, Xiong Su, Jialiu Liu, Sinju Sundaresan, and Philip D. Stahl. "Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is regulated by protein palmitoylation." Biochemical and Biophysical Research Communications 434, no. 2 (May 2013): 388–93. http://dx.doi.org/10.1016/j.bbrc.2013.04.001.

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Zhang, Pei, Lei Zhu, and Xiaodong Pan. "A comprehensive analysis of the oncogenic and prognostic role of TBC1Ds in human hepatocellular carcinoma." PeerJ 12 (May 14, 2024): e17362. http://dx.doi.org/10.7717/peerj.17362.

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Backgrounds TBC1D family members (TBC1Ds) are a group of proteins that contain the Tre2-Bub2-Cdc16 (TBC) domain. Recent studies have shown that TBC1Ds are involved in tumor growth, but no analysis has been done of expression patterns and prognostic values of TBC1Ds in hepatocellular carcinoma (HCC). Methods The expression levels of TBC1Ds were evaluated in HCC using the TIMER, UALCN and Protein Atlas databases. The correlation between the mRNA levels of TBC1Ds and the prognosis of patients with HCC in the GEPIA database was then analyzed. An enrichment analysis then revealed genes that potentially interact with TBC1Ds. The correlation between levels of TBC1Ds and tumor-infiltrating immune cells (TIICs) in HCC were studied using the TIMER 2.0 database. Finally, a series of in vitro assays verified the role of TBC1Ds in HCC progression. Results This study revealed the upregulated expression of TBC1Ds in HCC and the strong positive correlation between the mRNA levels of TBC1Ds and poor prognosis of patients with HCC. The functions of TBC1Ds were mainly related to autophagy and the AMPK pathway. There was also a significant correlation between level of TBC1Ds and tumor-infiltrating immune cells (TIICs) in HCC. The promoting role of TBC1Ds in HCC progression was verified in vitro assays. Conclusion The results of this analysis indicate that TBC1Ds may serve as new biomarkers for early diagnosis and treatment of HCC.

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Roach, William G., Jose A. Chavez, Cristinel P. Mîinea, and Gustav E. Lienhard. "Substrate specificity and effect on GLUT4 translocation of the Rab GTPase-activating protein Tbc1d1." Biochemical Journal 403, no. 2 (March 26, 2007): 353–58. http://dx.doi.org/10.1042/bj20061798.

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Insulin stimulation of the trafficking of the glucose transporter GLUT4 to the plasma membrane is controlled in part by the phosphorylation of the Rab GAP (GTPase-activating protein) AS160 (also known as Tbc1d4). Considerable evidence indicates that the phosphorylation of this protein by Akt (protein kinase B) leads to suppression of its GAP activity and results in the elevation of the GTP form of a critical Rab. The present study examines a similar Rab GAP, Tbc1d1, about which very little is known. We found that the Rab specificity of the Tbc1d1 GAP domain is identical with that of AS160. Ectopic expression of Tbc1d1 in 3T3-L1 adipocytes blocked insulin-stimulated GLUT4 translocation to the plasma membrane, whereas a point mutant with an inactive GAP domain had no effect. Insulin treatment led to the phosphorylation of Tbc1d1 on an Akt site that is conserved between Tbc1d1 and AS160. These results show that Tbc1d1 regulates GLUT4 translocation through its GAP activity, and is a likely Akt substrate. An allele of Tbc1d1 in which Arg125 is replaced by tryptophan has very recently been implicated in susceptibility to obesity by genetic analysis. We found that this form of Tbc1d1 also inhibited GLUT4 translocation and that this effect also required a functional GAP domain.

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Hodzic, Didier, Chen Kong, Marisa J. Wainszelbaum, Audra J. Charron, Xiong Su, and Philip D. Stahl. "TBC1D3, a hominoid oncoprotein, is encoded by a cluster of paralogues located on chromosome 17q12." Genomics 88, no. 6 (December 2006): 731–36. http://dx.doi.org/10.1016/j.ygeno.2006.05.009.

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Kong, Chen, Dmitri Samovski, Priya Srikanth, Marisa J. Wainszelbaum, Audra J. Charron, Jialiu Liu, Jeffrey J. Lange, et al. "Ubiquitination and Degradation of the Hominoid-Specific Oncoprotein TBC1D3 Is Mediated by CUL7 E3 Ligase." PLoS ONE 7, no. 9 (September 27, 2012): e46485. http://dx.doi.org/10.1371/journal.pone.0046485.

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He, Ze, Tian Tian, Dan Guo, Huijuan Wu, Yang Chen, Yongchen Zhang, Qing Wan, et al. "Cytoplasmic Retention of a Nucleocytoplasmic Protein TBC1D3 by Microtubule Network Is Required for Enhanced EGFR Signaling." PLoS ONE 9, no. 4 (April 8, 2014): e94134. http://dx.doi.org/10.1371/journal.pone.0094134.

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Jessen, Niels, Ding An, Aina S. Lihn, Jonas Nygren, Michael F. Hirshman, Anders Thorell, and Laurie J. Goodyear. "Exercise increases TBC1D1 phosphorylation in human skeletal muscle." American Journal of Physiology-Endocrinology and Metabolism 301, no. 1 (July 2011): E164—E171. http://dx.doi.org/10.1152/ajpendo.00042.2011.

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Exercise and weight loss are cornerstones in the treatment and prevention of type 2 diabetes, and both interventions function to increase insulin sensitivity and glucose uptake into skeletal muscle. Studies in rodents demonstrate that the underlying mechanism for glucose uptake in muscle involves site-specific phosphorylation of the Rab-GTPase-activating proteins AS160 (TBC1D4) and TBC1D1. Multiple kinases, including Akt and AMPK, phosphorylate TBC1D1 and AS160 on distinct residues, regulating their activity and allowing for GLUT4 translocation. In contrast to extensive rodent-based studies, the regulation of AS160 and TBC1D1 in human skeletal muscle is not well understood. In this study, we determined the effects of dietary intervention and a single bout of exercise on TBC1D1 and AS160 site-specific phosphorylation in human skeletal muscle. Ten obese (BMI 33.4 ± 2.4, M-value 4.3 ± 0.5) subjects were studied at baseline and after a 2-wk dietary intervention. Muscle biopsies were obtained from the subjects in the resting (basal) state and immediately following a 30-min exercise bout (70% V̇o2 max). Muscle lysates were analyzed for AMPK activity and Akt phosphorylation and for TBC1D1 and AS160 phosphorylation on known or putative AMPK and Akt sites as follows: AS160 Ser711 (AMPK), TBC1D1 Ser231 (AMPK), TBC1D1 Ser660 (AMPK), TBC1D1 Ser700 (AMPK), and TBC1D1 Thr590 (Akt). The diet intervention that consisted of a major shift in the macronutrient composition resulted in a 4.2 ± 0.4 kg weight loss ( P < 0.001) and a significant increase in insulin sensitivity ( M value 5.6 ± 0.6), but surprisingly, there was no effect on expression or phosphorylation of any of the muscle-signaling proteins. Exercise increased muscle AMPKα2 activity but did not increase Akt phosphorylation. Exercise increased phosphorylation on AS160 Ser711, TBC1D1 Ser231, and TBC1D1 Ser660 but had no effect on TBC1D1 Ser700. Exercise did not increase TBC1D1 Thr590 phosphorylation or TBC1D1/AS160 PAS phosphorylation, consistent with the lack of Akt activation. These data demonstrate that a single bout of exercise regulates TBC1D1 and AS160 phosphorylation on multiple sites in human skeletal muscle.

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Wang, Bei, Dandan Chen, and Haiying Hua. "TBC1D3 family is a prognostic biomarker and correlates with immune infiltration in kidney renal clear cell carcinoma." Molecular Therapy - Oncolytics 22 (September 2021): 528–38. http://dx.doi.org/10.1016/j.omto.2021.06.014.

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Zhou, Zhou, Franziska Menzel, Tim Benninghoff, Alexandra Chadt, Chen Du, Geoffrey D. Holman, and Hadi Al-Hasani. "Rab28 is a TBC1D1/TBC1D4 substrate involved in GLUT4 trafficking." FEBS Letters 591, no. 1 (December 20, 2016): 88–96. http://dx.doi.org/10.1002/1873-3468.12509.

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McMillin, Shawna L., Erin C. Stanley, Luke A. Weyrauch, Jeffrey J. Brault, Barbara B. Kahn, and Carol A. Witczak. "Insulin Resistance Is Not Sustained Following Denervation in Glycolytic Skeletal Muscle." International Journal of Molecular Sciences 22, no. 9 (May 6, 2021): 4913. http://dx.doi.org/10.3390/ijms22094913.

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Denervation rapidly induces insulin resistance (i.e., impairments in insulin-stimulated glucose uptake and signaling proteins) in skeletal muscle. Surprisingly, whether this metabolic derangement is long-lasting is presently not clear. The main goal of this study was to determine if insulin resistance is sustained in both oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles following long-term (28 days) denervation. Mouse hindlimb muscles were denervated via unilateral sciatic nerve resection. Both soleus and EDL muscles atrophied ~40%. Strikingly, while denervation impaired submaximal insulin-stimulated [3H]-2-deoxyglucose uptake ~30% in the soleus, it enhanced submaximal (~120%) and maximal (~160%) insulin-stimulated glucose uptake in the EDL. To assess possible mechanism(s), immunoblots were performed. Denervation did not consistently alter insulin signaling (e.g., p-Akt (Thr308):Akt; p-TBC1D1 [phospho-Akt substrate (PAS)]:TBC1D1; or p-TBC1D4 (PAS):TBC1D4) in either muscle. However, denervation decreased glucose transporter 4 (GLUT4) levels ~65% in the soleus but increased them ~90% in the EDL. To assess the contribution of GLUT4 to the enhanced EDL muscle glucose uptake, muscle-specific GLUT4 knockout mice were examined. Loss of GLUT4 prevented the denervation-induced increase in insulin-stimulated glucose uptake. In conclusion, the denervation results sustained insulin resistance in the soleus but enhanced insulin sensitivity in the EDL due to increased GLUT4 protein levels.

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Hatakeyama, Hiroyasu, Taisuke Morino, Takuya Ishii, and Makoto Kanzaki. "Cooperative actions of Tbc1d1 and AS160/Tbc1d4 in GLUT4-trafficking activities." Journal of Biological Chemistry 294, no. 4 (November 27, 2018): 1161–72. http://dx.doi.org/10.1074/jbc.ra118.004614.

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Wainszelbaum, Marisa J., Jialu Liu, Chen Kong, Priya Srikanth, Dmitri Samovski, Xiong Su, and Philip D. Stahl. "TBC1D3, a Hominoid-Specific Gene, Delays IRS-1 Degradation and Promotes Insulin Signaling by Modulating p70 S6 Kinase Activity." PLoS ONE 7, no. 2 (February 13, 2012): e31225. http://dx.doi.org/10.1371/journal.pone.0031225.

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Mann, Gagandeep, Michael C. Riddell, and Olasunkanmi A. J. Adegoke. "Effects of Acute Muscle Contraction on the Key Molecules in Insulin and Akt Signaling in Skeletal Muscle in Health and in Insulin Resistant States." Diabetology 3, no. 3 (July 28, 2022): 423–46. http://dx.doi.org/10.3390/diabetology3030032.

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Insulin signaling plays a key role in glucose uptake, glycogen synthesis, and protein and lipid synthesis. In insulin-resistant states like obesity and type 2 diabetes mellitus, these processes are dysregulated. Regular physical exercise is a potential therapeutic strategy against insulin resistance, as an acute bout of exercise increases glucose disposal during the activity and for hours into recovery. Chronic exercise increases the activation of proteins involved in insulin signaling and increases glucose transport, even in insulin resistant states. Here, we will focus on the effect of acute exercise on insulin signaling and protein kinase B (Akt) pathways. Activation of proximal proteins involved in insulin signaling (insulin receptor, insulin receptor substrate-1 (IRS-1), phosphoinoside-3 kinase (PI3K)) are unchanged in response to acute exercise/contraction, while activation of Akt and of its substrates, TBC1 domain family 1 (TBC1D1), and TBC domain family 4 (TBC1D4) increases in response to such exercise/contraction. A wide array of Akt substrates is also regulated by exercise. Additionally, AMP-activated protein kinase (AMPK) seems to be a main mediator of the benefits of exercise on skeletal muscle. Questions persist on how mTORC1 and AMPK, two opposing regulators, are both upregulated after an acute bout of exercise.

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Kothari, Charu, Alisson Clemenceau, Geneviève Ouellette, Kaoutar Ennour-Idrissi, Annick Michaud, René C.-Gaudreault, Caroline Diorio, and Francine Durocher. "TBC1D9: An Important Modulator of Tumorigenesis in Breast Cancer." Cancers 13, no. 14 (July 16, 2021): 3557. http://dx.doi.org/10.3390/cancers13143557.

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Triple-negative breast cancer (TNBC) is a major concern among the different subtypes of breast cancer (BC) due to the lack of effective treatment. In a previous study by our group aimed at understanding the difference between TNBC and non-TNBC tumors, we identified the gene TBC1 domain family member 9 (TBC1D9), the expression of which was lower in TNBC as compared to non-TNBC tumors. In the present study, analysis of TBC1D9 expression in TNBC (n = 58) and non-TNBC (n = 25) patient tumor samples validated that TBC1D9 expression can differentiate TNBC (low) from non-TNBC (high) samples and that expression of TBC1D9 was inversely correlated with grade and proliferative index. Moreover, we found that downregulation of the TBC1D9 gene decreases the proliferation marginally in non-TNBC and was associated with increased migratory and tumorigenic potential in both TNBC and luminal BC cell lines. This increase was mediated by the upregulation of ARL8A, ARL8B, PLK1, HIF1α, STAT3, and SPP1 expression in TBC1D9 knockdown cells. Our results suggest that TBC1D9 expression might limit tumor aggressiveness and that it has a differential expression in TNBC vs. non-TNBC tumors.

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Zhao, H. "18P TC-1 is required for TBC1D3-induced Wnt/beta-catenin accumulation and cell migration in MCF-7 breast cancer cells." Annals of Oncology 27 (December 2016): ix5. http://dx.doi.org/10.1016/s0923-7534(21)00180-0.

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Lipsey, Crystal C., Adriana Harbuzariu, Robert W. Robey, Lyn M. Huff, Michael M. Gottesman, and Ruben R. Gonzalez-Perez. "Leptin Signaling Affects Survival and Chemoresistance of Estrogen Receptor Negative Breast Cancer." International Journal of Molecular Sciences 21, no. 11 (May 27, 2020): 3794. http://dx.doi.org/10.3390/ijms21113794.

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Estrogen-receptor-negative breast cancer (BCER−) is mainly treated with chemotherapeutics. Leptin signaling can influence BCER− progression, but its effects on patient survival and chemoresistance are not well understood. We hypothesize that leptin signaling decreases the survival of BCER− patients by, in part, inducing the expression of chemoresistance-related genes. The correlation of expression of leptin receptor (OBR), leptin-targeted genes (CDK8, NANOG, and RBP-Jk), and breast cancer (BC) patient survival was determined from The Cancer Genome Atlas (TCGA) mRNA data. Leptin-induced expression of proliferation and chemoresistance-related molecules was investigated in triple-negative BC (TNBC) cells that respond differently to chemotherapeutics. Leptin-induced gene expression in TNBC was analyzed by RNA-Seq. The specificity of leptin effects was assessed using OBR inhibitors (shRNA and peptides). The results show that OBR and leptin-targeted gene expression are associated with lower survival of BCER− patients. Importantly, the co-expression of these genes was also associated with chemotherapy failure. Leptin signaling increased the expression of tumorigenesis and chemoresistance-related genes (ABCB1, WNT4, ADHFE1, TBC1D3, LL22NC03, RDH5, and ITGB3) and impaired chemotherapeutic effects in TNBC cells. OBR inhibition re-sensitized TNBC to chemotherapeutics. In conclusion, the co-expression of OBR and leptin-targeted genes may be used as a predictor of survival and drug resistance of BCER− patients. Targeting OBR signaling could improve chemotherapeutic efficacy.

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Sakamoto, Kei, and Geoffrey D. Holman. "Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic." American Journal of Physiology-Endocrinology and Metabolism 295, no. 1 (July 2008): E29—E37. http://dx.doi.org/10.1152/ajpendo.90331.2008.

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Vesicular traffic of the glucose transporter GLUT4 occurs in response to insulin, muscle contraction, and metabolic stimuli that lead to changes in the energy status of the cell. These stimuli are associated with linked kinase cascades that lead to changes in glucose uptake that meet the energy challenges imposed on the highly regulated cell types in insulin-responsive tissues. The need to mechanistically link these kinase-associated stimuli to identifiable intermediates in vesicular traffic has long been known but has been difficult to fulfill. The Rab-GTPase-activating proteins AS160 and TBC1D1 have now emerged as strong candidates to fill this void. Here we review the initial discovery of these proteins as phosphorylated substrates for Akt and the more recent emerging data that indicate that these proteins are substrates for additional kinases that are downstream of contraction and energy status signaling. The mechanism of coupling these phosphorylated proteins to vesicle traffic appears to be dependent on linking to small GTPase of the Rab family. We examine the current state of a hypothesis that suggests that phosphorylation of the Rab-GTPase-activating proteins leads to increased GTP loading of Rab proteins on GLUT4 vesicles and subsequently to increased interaction with Rab effectors that control GLUT4 vesicle translocation.

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Henriques, Andreia F. A., Paulo Matos, Ana Sofia Carvalho, Mikel Azkargorta, Felix Elortza, Rune Matthiesen, and Peter Jordan. "WNK1 phosphorylation sites in TBC1D1 and TBC1D4 modulate cell surface expression of GLUT1." Archives of Biochemistry and Biophysics 679 (January 2020): 108223. http://dx.doi.org/10.1016/j.abb.2019.108223.

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Wang, Bei, Huzi Zhao, Lei Zhao, Yongchen Zhang, Qing Wan, Yong Shen, Xiaodong Bu, Meiling Wan, and Chuanlu Shen. "Up-regulation of OLR1 expression by TBC1D3 through activation of TNFα/NF-κB pathway promotes the migration of human breast cancer cells." Cancer Letters 408 (November 2017): 60–70. http://dx.doi.org/10.1016/j.canlet.2017.08.021.

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Cartee, Gregory D. "Let's get real about the regulation of TBC1D1 and TBC1D4 phosphorylation in skeletal muscle." Journal of Physiology 592, no. 2 (January 2014): 253–54. http://dx.doi.org/10.1113/jphysiol.2013.269092.

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Zhao, Huzi, Lina Zhang, Yongchen Zhang, Lei Zhao, Qing Wan, Bei Wang, Xiaodong Bu, Meiling Wan, and Chuanlu Shen. "Calmodulin promotes matrix metalloproteinase 9 production and cell migration by inhibiting the ubiquitination and degradation of TBC1D3 oncoprotein in human breast cancer cells." Oncotarget 8, no. 22 (March 31, 2017): 36383–98. http://dx.doi.org/10.18632/oncotarget.16756.

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Park, Sang-Youn, and Soon-Jong Kim. "TBC1D1 and TBC1D4 (AS160) RabGAP Domains are Characterized as Monomers in Solution by Analytical Ultracentrifugation." Bulletin of the Korean Chemical Society 32, no. 6 (June 20, 2011): 2125–28. http://dx.doi.org/10.5012/bkcs.2011.32.6.2125.

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Castorena, Carlos M., James G. MacKrell, Makoto Kanzaki, Jonathan S. Bogan, and Gregory D. Cartee. "GLUT4, TBC1D1, TBC1D4, TUG and RUVBL2: Relationships with Each Other and Rat Muscle Fiber Type." Medicine & Science in Sports & Exercise 42 (October 2010): 12–13. http://dx.doi.org/10.1249/01.mss.0000389501.47832.4f.

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Cartee, Gregory D. "Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle." Diabetologia 58, no. 1 (October 4, 2014): 19–30. http://dx.doi.org/10.1007/s00125-014-3395-5.

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Schnurr, Theresia M., Emil Jørsboe, Alexandra Chadt, Inger K. Dahl-Petersen, Jonas M. Kristensen, Jørgen F. P. Wojtaszewski, Christian Springer, et al. "Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers." Diabetologia 64, no. 8 (April 29, 2021): 1795–804. http://dx.doi.org/10.1007/s00125-021-05461-z.

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Abstract Aims/hypothesis The common muscle-specific TBC1D4 p.Arg684Ter loss-of-function variant defines a subtype of non-autoimmune diabetes in Arctic populations. Homozygous carriers are characterised by elevated postprandial glucose and insulin levels. Because 3.8% of the Greenlandic population are homozygous carriers, it is important to explore possibilities for precision medicine. We aimed to investigate whether physical activity attenuates the effect of this variant on 2 h plasma glucose levels after an oral glucose load. Methods In a Greenlandic population cohort (n = 2655), 2 h plasma glucose levels were obtained after an OGTT, physical activity was estimated as physical activity energy expenditure and TBC1D4 genotype was determined. We performed TBC1D4–physical activity interaction analysis, applying a linear mixed model to correct for genetic admixture and relatedness. Results Physical activity was inversely associated with 2 h plasma glucose levels (β[main effect of physical activity] −0.0033 [mmol/l] / [kJ kg−1 day−1], p = 6.5 × 10−5), and significantly more so among homozygous carriers of the TBC1D4 risk variant compared with heterozygous carriers and non-carriers (β[interaction] −0.015 [mmol/l] / [kJ kg−1 day−1], p = 0.0085). The estimated effect size suggests that 1 h of vigorous physical activity per day (compared with resting) reduces 2 h plasma glucose levels by an additional ~0.7 mmol/l in homozygous carriers of the risk variant. Conclusions/interpretation Physical activity improves glucose homeostasis particularly in homozygous TBC1D4 risk variant carriers via a skeletal muscle TBC1 domain family member 4-independent pathway. This provides a rationale to implement physical activity as lifestyle precision medicine in Arctic populations. Data repository The Greenlandic Cardio-Metabochip data for the Inuit Health in Transition study has been deposited at the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/dacs/EGAC00001000736) under accession EGAD00010001428. Graphical abstract

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Gunsilius, Harald, Horst Borrmann, Arndt Simon, and Werner Urland. "Zur Polymorphie von TbCI3/ Polymorphism of TbCl3." Zeitschrift für Naturforschung B 43, no. 8 (August 1, 1988): 1023–28. http://dx.doi.org/10.1515/znb-1988-0819.

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Abstract3 different modifications of TbCl3 were synthesized. TbCl, (UCl3-type), probably in a metastable state, crystallizes in space group P63/m with a = 737.63(2) pm, c = 405.71(2) pm and Z - 2. TbCl3 (PuB3-type) crystallizes in space group Cmcm with a = 384.71(6) pm, b = 1177.37(7) pm. c = 851.77(4) pm and Z = 4. h-TbCl3, the high temperature phase being stable above 790 K. crystallizes in space group P42/mnm with a = 642.51(4) pm, c = 1177.14(18) pm and Z = 4.

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Zhang, Jianxian, Yan Xue, Hengling Gao, Yunxi Yu, Huabin Cheng, Xukun Lv, and Ke Ke. "circZC3HAV1 Regulates TBC1D9 to Affect the Biological Behavior of Colorectal Cancer Cells." BioMed Research International 2022 (September 16, 2022): 1–17. http://dx.doi.org/10.1155/2022/7386946.

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Background. Colorectal cancer (CRC) is one of the most frequently diagnosed cancers all over the world, which accounts for a large proportion of cancer-associated deaths. The regulatory function of circular RNAs (circRNAs) has been affirmed in diverse cancers. circ_0082628, named circRNA zinc finger CCCH-type containing antiviral 1 (circZC3HAV1), has been discovered to be significantly downregulated in CRC tissues. Nevertheless, the function and mechanism of circZC3HAV1 in CRC remain unclear. Purpose. We targeted at studying the specific role and mechanism of circZC3HAV1 in CRC cells. Methods. The expression of the genes was detected by quantitative real-time polymerase chain reaction (qPCR). The binding relationship among different genes was verified by mechanism assays. Functional assays were carried out to reveal the role of different RNAs in CRC cell malignant behaviors. Results. circZC3HAV1 was significantly downregulated in CRC cells. circZC3HAV1 overexpression hampered CRC cell migratory and invasive abilities. As for the mechanism, circZC3HAV1 competitively bound with microRNA-146b-3p (miR-146b-3p) to enhance the expression of TBC1 domain family member 9 (TBC1D9). Rescue assays demonstrated circZC3HAV1 sponged miR-146b-3p and upregulated TBC1D9 to restrict migration and invasion of CRC cells. Conclusion. circZC3HAV1 could upregulate TBC1D9 via absorbing miR-146b-3p, consequently inhibiting migratory and invasive capabilities of CRC cells.

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Chang, Wen-Lin, Lina Cui, Yanli Gu, Minghua Li, Qian Ma, Zeng Zhang, Jing Ye, Fangting Zhang, Jing Yu, and Yaoting Gui. "TBC1D20 deficiency induces Sertoli cell apoptosis by triggering irreversible endoplasmic reticulum stress in mice." Molecular Human Reproduction 25, no. 12 (October 21, 2019): 773–86. http://dx.doi.org/10.1093/molehr/gaz057.

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Abstract Male ‘blind sterile’ mice with the causative TBC1 domain family member 20 (TBC1D20) deficiency are infertile with excessive germ cell apoptosis and spermatogenesis arrest at the spermatid stage. Sertoli cells are characterised as ‘nurse cells’ essential for normal spermatogenesis, but the role and corresponding molecular mechanisms of TBC1D20 deficiency in Sertoli cells of mice are not clear to date. In the present study, the histopathology of the testis and Sertoli cell proliferation and apoptosis were determined, and the corresponding molecular mechanisms were investigated by western blotting. Our data showed that TBC1D20 exhibits a testis-abundant expression pattern, and its expression level is positively associated with spermatogenesis. TBC1D20 is assembled in the Golgi and endoplasmic reticulum and is widely expressed by various germ cell subtypes and Sertoli cells. TBC1D20 deficiency in Sertoli cells led to an excessive apoptosis ratio and G1/S arrest. The increased apoptosis of TBC1D20-deficient Sertoli cells resulted from caspase-12 activation. TBC1D20-deficient Sertoli cells had an abnormal Golgi-endoplasmic reticulum structure, which led to endoplasmic reticulum stress, resulting in cell cycle arrest and excessive apoptosis. It suggested that TBC1D20 deficiency triggers irreversible endoplasmic reticulum stress resulting in G1/S arrest and excessive apoptosis in TBC1D20-deficient Sertoli cells, and TBC1D20 deficiency in Sertoli cells may also contribute to the infertility phenotype in ‘blind sterile’ male mice.

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Zhou, Z., F. Menzel, T. Benninghoff, A. Chadt, C. Du, GD Holman, and H. Al-Hasani. "Rab28 ist ein neu beschriebenes Substrat für TBC1D1/TBC1D4 und beteiligt an der regulierten Translokation von GLUT4." Diabetologie und Stoffwechsel 12, S 01 (May 5, 2017): S1—S84. http://dx.doi.org/10.1055/s-0037-1601642.

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Treebak, Jonas T., Christian Pehmøller, Jonas M. Kristensen, Rasmus Kjøbsted, Jesper B. Birk, Peter Schjerling, Erik A. Richter, Laurie J. Goodyear, and Jørgen F. P. Wojtaszewski. "Acute exercise and physiological insulin induce distinct phosphorylation signatures on TBC1D1 and TBC1D4 proteins in human skeletal muscle." Journal of Physiology 592, no. 2 (December 23, 2013): 351–75. http://dx.doi.org/10.1113/jphysiol.2013.266338.

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Fukuda, Mitsunori. "TBC proteins: GAPs for mammalian small GTPase Rab?" Bioscience Reports 31, no. 3 (January 14, 2011): 159–68. http://dx.doi.org/10.1042/bsr20100112.

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The TBC (Tre-2/Bub2/Cdc16) domain was originally identified as a conserved domain among the tre-2 oncogene product and the yeast cell cycle regulators Bub2 and Cdc16, and it is now widely recognized as a conserved protein motif that consists of approx. 200 amino acids in all eukaryotes. Since the TBC domain of yeast Gyps [GAP (GTPase-activating protein) for Ypt proteins] has been shown to function as a GAP domain for small GTPase Ypt/Rab, TBC domain-containing proteins (TBC proteins) in other species are also expected to function as a certain Rab-GAP. More than 40 different TBC proteins are present in humans and mice, and recent accumulating evidence has indicated that certain mammalian TBC proteins actually function as a specific Rab-GAP. Some mammalian TBC proteins {e.g. TBC1D1 [TBC (Tre-2/Bub2/Cdc16) domain family, member 1] and TBC1D4/AS160 (Akt substrate of 160 kDa)} play an important role in homoeostasis in mammals, and defects in them are directly associated with mouse and human diseases (e.g. leanness in mice and insulin resistance in humans). The present study reviews the structure and function of mammalian TBC proteins, especially in relation to Rab small GTPases.

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Peifer-Weiß, Leon, Hadi Al-Hasani, and Alexandra Chadt. "AMPK and Beyond: The Signaling Network Controlling RabGAPs and Contraction-Mediated Glucose Uptake in Skeletal Muscle." International Journal of Molecular Sciences 25, no. 3 (February 5, 2024): 1910. http://dx.doi.org/10.3390/ijms25031910.

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Impaired skeletal muscle glucose uptake is a key feature in the development of insulin resistance and type 2 diabetes. Skeletal muscle glucose uptake can be enhanced by a variety of different stimuli, including insulin and contraction as the most prominent. In contrast to the clearance of glucose from the bloodstream in response to insulin stimulation, exercise-induced glucose uptake into skeletal muscle is unaffected during the progression of insulin resistance, placing physical activity at the center of prevention and treatment of metabolic diseases. The two Rab GTPase-activating proteins (RabGAPs), TBC1D1 and TBC1D4, represent critical nodes at the convergence of insulin- and exercise-stimulated signaling pathways, as phosphorylation of the two closely related signaling factors leads to enhanced translocation of glucose transporter 4 (GLUT4) to the plasma membrane, resulting in increased cellular glucose uptake. However, the full network of intracellular signaling pathways that control exercise-induced glucose uptake and that overlap with the insulin-stimulated pathway upstream of the RabGAPs is not fully understood. In this review, we discuss the current state of knowledge on exercise- and insulin-regulated kinases, hypoxia, nitric oxide (NO) and bioactive lipids that may be involved in the regulation of skeletal muscle glucose uptake.

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Hargett, Stefan R., Natalie N. Walker, and Susanna R. Keller. "Rab GAPs AS160 and Tbc1d1 play nonredundant roles in the regulation of glucose and energy homeostasis in mice." American Journal of Physiology-Endocrinology and Metabolism 310, no. 4 (February 15, 2016): E276—E288. http://dx.doi.org/10.1152/ajpendo.00342.2015.

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The related Rab GTPase-activating proteins (Rab GAPs) AS160 and Tbc1d1 regulate the trafficking of the glucose transporter GLUT4 that controls glucose uptake in muscle and fat cells and glucose homeostasis. AS160- and Tbc1d1-deficient mice exhibit different adipocyte- and skeletal muscle-specific defects in glucose uptake, GLUT4 expression and trafficking, and glucose homeostasis. A recent study analyzed male mice with simultaneous deletion of AS160 and Tbc1d1 (AS160−/−/Tbc1d1−/− mice). Herein, we describe abnormalities in male and female AS160−/−/Tbc1d1−/− mice on another strain background. We confirm the earlier observation that GLUT4 expression and glucose uptake defects of single-knockout mice join in AS160−/−/Tbc1d1−/− mice to affect all skeletal muscle and adipose tissues. In large mixed fiber-type skeletal muscles, changes in relative basal GLUT4 plasma membrane association in AS160−/− and Tbc1d1−/− mice also combine in AS160−/−/Tbc1d1−/− mice. However, we found different glucose uptake abnormalities in isolated skeletal muscles and adipocytes than reported previously, resulting in different interpretations of how AS160 and Tbc1d1 regulate GLUT4 translocation to the cell surface. In support of a larger role for AS160 in glucose homeostasis, in contrast with the previous study, we find similarly impaired glucose and insulin tolerance in AS160−/−/Tbc1d1−/− and AS160−/− mice. However, in vivo glucose uptake abnormalities in AS160−/−/Tbc1d1−/− skeletal muscles differ from those observed previously in AS160−/− mice, indicating additional defects due to Tbc1d1 deletion. Similar to AS160- and Tbc1d1-deficient mice, AS160−/−/Tbc1d1−/− mice show sex-specific abnormalities in glucose and energy homeostasis. In conclusion, our study supports nonredundant functions for AS160 and Tbc1d1.

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Chadt, Alexandra, Anja Immisch, Christian de Wendt, Christian Springer, Zhou Zhou, Torben Stermann, Geoffrey D. Holman, et al. "Deletion of Both Rab-GTPase–Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport." Diabetes 64, no. 3 (September 23, 2014): 746–59. http://dx.doi.org/10.2337/db14-0368.

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Park, Sang-Youn, Wanzhu Jin, Ju Rang Woo, and Steven E. Shoelson. "Crystal Structures of Human TBC1D1 and TBC1D4 (AS160) RabGTPase-activating Protein (RabGAP) Domains Reveal Critical Elements for GLUT4 Translocation." Journal of Biological Chemistry 286, no. 20 (March 23, 2011): 18130–38. http://dx.doi.org/10.1074/jbc.m110.217323.

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Di Chiara, Marianna, Bob Glaudemans, Dominique Loffing-Cueni, Alex Odermatt, Hadi Al-Hasani, Olivier Devuyst, Nourdine Faresse, and Johannes Loffing. "Rab-GAP TBC1D4 (AS160) is dispensable for the renal control of sodium and water homeostasis but regulates GLUT4 in mouse kidney." American Journal of Physiology-Renal Physiology 309, no. 9 (November 1, 2015): F779—F790. http://dx.doi.org/10.1152/ajprenal.00139.2015.

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The Rab GTPase-activating protein TBC1D4 (AS160) controls trafficking of the glucose transporter GLUT4 in adipocytes and skeletal muscle cells. TBC1D4 is also highly abundant in the renal distal tubule, although its role in this tubule is so far unknown. In vitro studies suggest that it is involved in the regulation of renal transporters and channels such as the epithelial sodium channel (ENaC), aquaporin-2 (AQP2), and the Na+-K+-ATPase. To assess the physiological role of TBC1D4 in the kidney, wild-type (TBC1D4+/+) and TBC1D4-deficient (TBC1D4−/−) mice were studied. Unexpectedly, neither under standard nor under challenging conditions (low Na+/high K+, water restriction) did TBC1D4−/−mice show any difference in urinary Na+and K+excretion, urine osmolarity, plasma ion and aldosterone levels, and blood pressure compared with TBC1D4+/+mice. Also, immunoblotting did not reveal any change in the abundance of major renal sodium- and water-transporting proteins [Na-K-2Cl cotransporter (NKCC2) NKCC2, NaCl cotransporter (NCC), ENaC, AQP2, and the Na+-K+-ATPase]. However, the abundance of GLUT4, which colocalizes with TBC1D4 along the distal nephron of TBC1D4+/+mice, was lower in whole kidney lysates of TBC1D4−/−mice than in TBC1D4+/+mice. Likewise, primary thick ascending limb (TAL) cells isolated from TBC1D4−/−mice showed an increased basal glucose uptake and an abrogated insulin response compared with TAL cells from TBC1D4+/+mice. Thus, TBC1D4 is dispensable for the regulation of renal Na+and water transport, but may play a role for GLUT4-mediated basolateral glucose uptake in distal tubules. The latter may contribute to the known anaerobic glycolytic capacity of distal tubules during renal ischemia.

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Hargett, Stefan R., Natalie N. Walker, Syed S. Hussain, Kyle L. Hoehn, and Susanna R. Keller. "Deletion of the Rab GAP Tbc1d1 modifies glucose, lipid, and energy homeostasis in mice." American Journal of Physiology-Endocrinology and Metabolism 309, no. 3 (August 1, 2015): E233—E245. http://dx.doi.org/10.1152/ajpendo.00007.2015.

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Tbc1d1 is a Rab GTPase-activating protein (GAP) implicated in regulating intracellular retention and cell surface localization of the glucose transporter GLUT4 and thus glucose uptake in a phosphorylation-dependent manner. Tbc1d1 is most abundant in skeletal muscle but is expressed at varying levels among different skeletal muscles. Previous studies with male Tbc1d1-deficient (Tbc1d1−/−) mice on standard and high-fat diets established a role for Tbc1d1 in glucose, lipid, and energy homeostasis. Here we describe similar, but also additional abnormalities in male and female Tbc1d1−/− mice. We corroborate that Tbc1d1 loss leads to skeletal muscle-specific and skeletal muscle type-dependent abnormalities in GLUT4 expression and glucose uptake in female and male mice. Using subcellular fractionation, we show that Tbc1d1 controls basal intracellular GLUT4 retention in large skeletal muscles. However, cell surface labeling of extensor digitorum longus muscle indicates that Tbc1d1 does not regulate basal GLUT4 cell surface exposure as previously suggested. Consistent with earlier observations, female and male Tbc1d1−/− mice demonstrate increased energy expenditure and skeletal muscle fatty acid oxidation. Interestingly, we observe sex-dependent differences in in vivo phenotypes. Female, but not male, Tbc1d1−/− mice have decreased body weight and impaired glucose and insulin tolerance, but only male Tbc1d1−/− mice show increased lipid clearance after oil gavage. We surmise that similar changes at the tissue level cause differences in whole-body metabolism between male and female Tbc1d1−/− mice and between male Tbc1d1−/− mice in different studies due to variations in body composition and nutrient handling.

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Pehmøller, Christian, Jonas T. Treebak, Jesper B. Birk, Shuai Chen, Carol MacKintosh, D. Grahame Hardie, Erik A. Richter, and Jørgen F. P. Wojtaszewski. "Genetic disruption of AMPK signaling abolishes both contraction- and insulin-stimulated TBC1D1 phosphorylation and 14-3-3 binding in mouse skeletal muscle." American Journal of Physiology-Endocrinology and Metabolism 297, no. 3 (September 2009): E665—E675. http://dx.doi.org/10.1152/ajpendo.00115.2009.

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TBC1D1 is a Rab-GTPase-activating protein (GAP) known to be phosphorylated in response to insulin, growth factors, pharmacological agonists that activate 5′-AMP-activated protein kinase (AMPK), and muscle contraction. Silencing TBC1D1 in L6 muscle cells by siRNA increases insulin-stimulated GLUT4 translocation, and overexpression of TBC1D1 in 3T3-L1 adipocytes with low endogenous TBC1D1 expression inhibits insulin-stimulated GLUT4 translocation, suggesting a role of TBC1D1 in regulating GLUT4 translocation. Aiming to unravel the regulation of TBC1D1 during contraction and the potential role of AMPK in intact skeletal muscle, we used EDL muscles from wild-type (WT) and AMPK kinase dead (KD) mice. We explored the site-specific phosphorylation of TBC1D1 Ser237 and Thr596 and their relation to 14-3-3 binding, a proposed mechanism for regulation of GAP function of TBC1D1. We show that muscle contraction increases 14-3-3 binding to TBC1D1 as well as phosphorylation of Ser237 and Thr596 in an AMPK-dependent manner. AMPK activation by AICAR induced similar Ser237 and Thr596 phosphorylation of, and 14-3-3 binding to, TBC1D1 as muscle contraction. Insulin did not increase Ser237 phosphorylation or 14-3-3 binding to TBC1D1. However, insulin increased Thr596 phosphorylation, and intriguingly this response was fully abolished in the AMPK KD mice. Thus, TBC1D1 is differentially regulated in response to insulin and contraction. This study provides genetic evidence to support an important role for AMPK in regulating TBC1D1 in response to both of these physiological stimuli.

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Vichaiwong, Kanokwan, Suneet Purohit, Ding An, Taro Toyoda, Niels Jessen, Michael F. Hirshman, and Laurie J. Goodyear. "Contraction regulates site-specific phosphorylation of TBC1D1 in skeletal muscle." Biochemical Journal 431, no. 2 (September 28, 2010): 311–20. http://dx.doi.org/10.1042/bj20101100.

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TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family member 1) is a Rab-GAP (GTPase-activating protein) that is highly expressed in skeletal muscle, but little is known about TBC1D1 regulation and function. We studied TBC1D1 phosphorylation on three predicted AMPK (AMP-activated protein kinase) phosphorylation sites (Ser231, Ser660 and Ser700) and one predicted Akt phosphorylation site (Thr590) in control mice, AMPKα2 inactive transgenic mice (AMPKα2i TG) and Akt2-knockout mice (Akt2 KO). Muscle contraction significantly increased TBC1D1 phosphorylation on Ser231 and Ser660, tended to increase Ser700 phosphorylation, but had no effect on Thr590. AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside) also increased phosphorylation on Ser231, Ser660 and Ser700, but not Thr590, whereas insulin only increased Thr590 phosphorylation. Basal and contraction-stimulated TBC1D1 Ser231, Ser660 and Ser700 phosphorylation were greatly reduced in AMPKα2i TG mice, although contraction still elicited a small increase in phosphorylation. Akt2 KO mice had blunted insulin-stimulated TBC1D1 Thr590 phosphorylation. Contraction-stimulated TBC1D1 Ser231 and Ser660 phosphorylation were normal in high-fat-fed mice. Glucose uptake in vivo was significantly decreased in tibialis anterior muscles overexpressing TBC1D1 mutated on four predicted AMPK phosphorylation sites. In conclusion, contraction causes site-specific phosphorylation of TBC1D1 in skeletal muscle, and TBC1D1 phosphorylation on AMPK sites regulates contraction-stimulated glucose uptake. AMPK and Akt regulate TBC1D1 phosphorylation, but there must be additional upstream kinases that mediate TBC1D1 phosphorylation in skeletal muscle.

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Gutierrez, Jorge A., Christian M. Shannon, Shaun A. Nguyen, Ted A. Meyer, and Paul R. Lambert. "Comparison of Transcutaneous and Percutaneous Implantable Hearing Devices for the Management of Congenital Aural Atresia: A Systematic Review and Meta-Analysis." Otology & Neurotology 45, no. 1 (November 26, 2023): 1–10. http://dx.doi.org/10.1097/mao.0000000000004061.

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Objective To compare audiometric outcomes, complications, and revisions required for percutaneous (pBCD) versus transcutaneous (tBCD) implantable bone-conduction devices for the treatment of hearing loss associated with congenital aural atresia (CAA). Databases Reviewed. PubMed, Scopus, CINAHL. Methods A systematic review was performed searching for English language articles from inception to December 14, 2022. Studies reporting audiometric outcomes or complications for either pBCDs or tBCDs for the treatment of CAA were selected for inclusion. A meta-analysis of single means and meta-analysis of proportions with comparison (Δ) of weighted proportions was conducted. Results A total of 56 articles with 756 patients were selected for inclusion. One hundred ninety patients were implanted with pBCDs, whereas the remaining 566 were implanted with tBCDs. Mean pure-tone audiometry improvement in the pBCD group (39.1 ± 1.1 dB) was significantly higher than in the tBCD group (34.6 ± 1.6 dB; Δ4.5 dB; 95% confidence interval, 4.2–4.7 dB; p < 0.0001). The average improvement in speech reception threshold was 38.6 ± 2.5 dB in the percutaneous group as compared with 32.7 ± 1.6 dB in the transcutaneous group (Δ5.9 dB [5.3–6.5 dB], p < 0.0001). Overall complication rates for patients implanted with pBCDs and tBCDs were 29.0% (15.7–44.4%) and 9.4% (6.5%–13.0%), respectively (Δ19.6% [12.0–27.7%], p < 0.0001). Conclusions Patients with CAA implanted with pBCDs had significantly better audiometric outcomes than those implanted with tBCDs. However, complication rates were significantly higher among the pBCD group.

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Mafakheri, Samaneh, Ralf R. Flörke, Sibylle Kanngießer, Sonja Hartwig, Lena Espelage, Christian De Wendt, Tina Schönberger, et al. "AKT and AMP-activated protein kinase regulate TBC1D1 through phosphorylation and its interaction with the cytosolic tail of insulin-regulated aminopeptidase IRAP." Journal of Biological Chemistry 293, no. 46 (October 1, 2018): 17853–62. http://dx.doi.org/10.1074/jbc.ra118.005040.

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Abstract:

In skeletal muscle, the Rab GTPase-activating (GAP) protein TBC1D1 is phosphorylated by AKT and AMP-activated protein kinase (AMPK) in response to insulin and muscle contraction. Genetic ablation of Tbc1d1 or mutation of distinct phosphorylation sites impairs intracellular GLUT4 retention and GLUT4 traffic, presumably through alterations of the activation state of downstream Rab GTPases. Previous studies have focused on characterizing the C-terminal GAP domain of TBC1D1 that lacks the known phosphorylation sites, as well as putative regulatory domains. As a result, it has been unclear how phosphorylation of TBC1D1 would regulate its activity. In the present study, we have expressed, purified, and characterized recombinant full-length TBC1D1 in Sf9 insect cells via the baculovirus system. Full-length TBC1D1 showed RabGAP activity toward GLUT4-associated Rab8a, Rab10, and Rab14, indicating similar substrate specificity as the truncated GAP domain. However, the catalytic activity of the full-length TBC1D1 was markedly higher than that of the GAP domain. Although in vitro phosphorylation of TBC1D1 by AKT or AMPK increased 14-3-3 binding, it did not alter the intrinsic RabGAP activity. However, we found that TBC1D1 interacts through its N-terminal PTB domains with the cytoplasmic domain of the insulin-regulated aminopeptidase, a resident protein of GLUT4 storage vesicles, and this binding is disrupted by phosphorylation of TBC1D1 by AKT or AMPK. In summary, our findings suggest that other regions outside the GAP domain may contribute to the catalytic activity of TBC1D1. Moreover, our data indicate that recruitment of TBC1D1 to GLUT4-containing vesicles and not its GAP activity is regulated by insulin and contraction-mediated phosphorylation.

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