Academic literature on the topic 'PTPN11, tyrosine protein phosphatase non-receptor type 11'

In the current study we carried out computational drug designing and dock-ing studies on Tyrosine-protein phosphatase non-receptor type 11 (PTPN11). Scaffold selection was based on the functional properties of PTPN11. Leads were identified based on several physiochemical properties and we created our library with those new molecules that were generated based on Lipinski's rule of five. Further, we carried out high throughput screening on 21 molecules from scaffolds selected. Screening of molecules was based on the criterions such as, TOPKAT (toxicity analysis) and ADMET (absorption, distribution, metabolism, elimination) properties. Among the ligands de-signed, only one compound was identified to have premium interaction within the targeted domain. Pharmacophore was generated and analyzed for selected drug candidate. Our results suggest that O-(3-hydroxy-4-methoxyphenyl) S-methyl dithio dicarbonate is a potent drug molecule in terms of physiochemical and docking properties. In conclusion, the identified compound has great potential to inhibit tyrosine-protein phosphatase non-receptor type 11 (PTPN11).

Anti-ulcer medicines that inhibit the H/K-ATPase enzyme by covalently binding to a cysteine residue of proton pump inhibitors. Through the aforementioned processes, tyrosine-protein phosphatase non-receptor type 11 (PTPN11) causes aberrant mitogenic signals and elongated morphological alterations, as well as the growth and progression of peptic ulcer and gastric cancer.Piperine is an antioxidant derived from the Piper Longum herb. Molecular docking studies and virtual screening were used to investigate it as an H/K ATPase and PTPN11 inhibitor. The Molecular Docking examination was conducted using the Pyrx 0.8 version free database, while virtual screening was conducted using Biovia Discovery Studio software.H/K-ATPase and PTPN11 have substantial binding affinity of 7.5 and 8.6 kcal/mol, respectively, according to molecular docking investigations. Piperine's anti-ulcer efficacy appears to be aided by H/K-ATPase and PTPN11 binding

ContextNoonan syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. Short-term effect of GH therapy in NS is beneficial, reports on the effect on adult height are scarce.ObjectiveTo determine the effect of long-term GH therapy in children with NS.DesignTwenty-nine children with NS were treated with GH until final height was reached.SettingHospital endocrinology departments.PatientsChildren with the clinical diagnosis of NS, with mean age at the start of therapy of 11.0 years, 22 out of 27 tested children had a mutation in the protein tyrosine phosphatase, non-receptor-type 11 gene (PTPN11 gene).InterventionsGH was administered subcutaneously at 0.05 mg/kg per day until growth velocity was 1 cm/6 months.Main outcome measureLinear growth (height) was measured at 3-month intervals in the first year and at 6-month intervals thereafter until final height.ResultsAt the start of treatment, median height SDS (H-SDS) was −2.8 (−4.1 to −1.8) and 0.0 (−1.4 to +1.2), based on national and Noonan standards respectively. GH therapy lasted for 3.0–10.3 years (median, 6.4), producing mean gains in H-SDS of +1.3 (+0.2 to +2.7) and +1.3 (−0.6 to +2.4), based on national and Noonan standards respectively. In 22 children with a mutation in PTPN11 mean gain in H-SDS for National standards was +1.3, not different from the mean gain in the five children without a mutation in PTPN11+1.3 (P=0.98).ConclusionLong-term GH treatment in NS leads to attainment of adult height within the normal range in most patients.

Abstract Prognostic factors associated with chemotherapy outcomes in patients with acute myeloid leukemia (AML) are extensively reported, and one gene whose mutation is recognized as conferring resistance to several newer targeted therapies is protein tyrosine phosphatase non-receptor type 11 (PTPN11). The broader clinical implications of PTPN11 mutations in AML are still not well understood. The objective of this study was to determine which cytogenetic abnormalities and gene mutations co-occur with PTPN11 mutations and how PTPN11 mutations affect outcomes of patients treated with intensive chemotherapy. We studied 1725 patients newly diagnosed with AML (excluding acute promyelocytic leukemia) enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. In 140 PTPN11-mutated patient samples, PTPN11 most commonly co-occurred with mutations in NPM1, DNMT3A, and TET2. PTPN11 mutations were relatively common in patients with an inv(3)(q21q26)/t(3;3)(q21;q26) and a normal karyotype but were very rare in patients with typical complex karyotype and core-binding factor AML. Mutations in the N-terminal SH2 domain of PTPN11 were associated with a higher early death rate than those in the phosphatase domain. PTPN11 mutations did not affect outcomes of NPM1-mutated patients, but these patients were less likely to have co-occurring kinase mutations (ie, FLT3-ITD), suggesting activation of overlapping signaling pathways. However, in AML patients with wild-type NPM1, PTPN11 mutations were associated with adverse patient outcomes, providing a rationale to study the biology and treatment approaches in this molecular group. This trial was registered at www.clinicaltrials.gov as #NCT00048958 (CALGB 8461), #NCT00899223 (CALGB 9665), and #NCT00900224 (CALGB 20202).

This study was aimed to investigate the role of SHP2 (Src-homology-2-containing phosphotyrosine phosphatase) in intricate signaling networks invoked by bovine oocyte to achieve maturation and blastocyst development. PTPN11 (Protein Tyrosine Phosphatase, non-receptor type 11) encoding protein SHP2, a positive transducer of RTKs (Receptor Tyrosine Kinases) and cytokine receptors, can play a significant role in bovine oocyte maturation and embryo development, but this phenomenon has not yet been explored. Here, we used different growth factors, cytokines, selective activator, and a specific inhibitor of SHP2 to ascertain its role in bovine oocyte developmental stages in vitro. We found that SHP2 became activated by growth factors and cytokines treatment and was highly involved in the activation of oocyte maturation and embryo development pathways. Activation of SHP2 triggered MAPK (mitogen-activated protein kinases) and PI3K/AKT (Phosphoinositide 3-kinase/Protein kinase B) signaling cascades, which is not only important for GVBD (germinal vesical breakdown) induction but also for maternal mRNA translation. Inhibition of phosphatase activity of SHP2 with PHPS1 (Phenylhydrazonopyrazolone sulfonate 1) reduced oocytes maturation as well as bovine blastocyst ICM (inner cell mass) volume. Supplementation of LIF (Leukemia Inhibitory Factor) to embryos showed an unconventional direct relation between p-SHP2 and p-STAT3 (Signal transducer and activator of transcription 3) for blastocyst ICM development. Other than growth factors and cytokines, cisplatin was used to activate SHP2. Cisplatin activated SHP2 modulate growth factors effect and combine treatment significantly enhanced quality and rate of developed blastocysts.

The molecular mechanisms for hypoxic environment causing the injury of intestinal mucosal barrier (IMB) are widely unknown. To address the issue, Han Chinese from 100 m altitude and Tibetans from high altitude (more than 3650 m) were recruited. Histological and transcriptome analyses were performed. The results showed intestinal villi were reduced and appeared irregular, and glandular epithelium was destroyed in the IMB of Tibetans when compared with Han Chinese. Transcriptome analysis revealed 2573 genes with altered expression. The levels of 1137 genes increased and 1436 genes decreased in Tibetans when compared with Han Chinese. Gene ontology (GO) analysis indicated most immunological responses were reduced in the IMB of Tibetans when compared with Han Chinese. Gene microarray showed that there were 25-, 22-, and 18-fold downregulation for growth factor receptor-bound protein 2 (GRB2), epidermal growth factor receptor (EGFR), and tyrosine-protein phosphatase nonreceptor type 11 (PTPN11) in the IMB of Tibetans when compared with Han Chinese. The downregulation of EGFR, GRB2, and PTPN11 will reduce the production of reactive oxygen species and protect against oxidative stress-induced injury for intestine. Thus, the transcriptome analysis showed the protecting functions of IMB patients against hypoxia-induced oxidative injury in the intestine of Tibetans via affecting GRB2/EGFR/PTPN11 pathways.

Abstract Context: Noonan syndrome is frequently associated with an unclear disturbance of GH secretion. Half the individuals with Noonan syndrome carry a heterozygous mutation of the nonreceptor-type protein tyrosine phosphatase, Src homology region 2-domain phosphatase-2 (SHP-2), encoded by PTPN11, which has a role in GH receptor signaling. Objective: The objective of this study was to compare GH secretion and IGF-I/IGF-binding protein-3 (IGFBP-3) levels of the SHP-2 mutation-positive (mut+ group) vs. mutation-negative individuals (mut− group). Design, Setting, and Patients: All children presenting to us with short stature plus at least three typical anomalies of Noonan syndrome or pulmonic stenosis during the last 5 yr (n = 29; 10 females and 19 males) were recruited. Auxological data, dysmorphic features, and cardiac morphology were documented. Hormone levels were measured by RIA. All coding exons of PTPN11 were sequenced after PCR amplification. Intervention: A prepubertal subgroup (n = 11) was treated with recombinant human GH (rhGH) to promote growth. Results: Sequencing yielded 11 different PTPN11 missense mutations in 16 of the 29 patients (55% mut+). Pulmonic stenosis (81 vs. 15%; P = 0.0007) and septal defects (63 vs. 15%; P = 0.02) were more frequently found in the mut+ group, whereas minor anomalies, cryptorchidism, and learning disabilities were as frequent in the mut+ group as in the mut− group. The mut+ group was younger at presentation (mean ± sd, 5.1 ± 2.7 vs. 10.3 ± 5.2 yr; P = 0.002), but not significantly shorter [−3.15 ± 0.92 vs. −3.01 ± 1.35 height sd score (SDS)]. IGF-I levels (−2.03 ± 0.69 vs. −1.13 ± 0.89 SDS; P = 0.005) and IGFBP-3 levels (−0.92 ± 1.26 vs. 0.40 ± 1.08 SDS; P = 0.006) were significantly lower in the mut+ group. In contrast, GH levels showed a tendency to be higher in the mut+ group during spontaneous secretion at night and arginine stimulation (P ≥ 0.075, not significant). The mean change in height SDS after 1 yr of rhGH therapy (0.043 mg/kg·d) was +0.66 ± 0.21 in the mut+ group (n = 8), but +1.26 ± 0.36 in the mut− group (n = 3; P = 0.007). Conclusions: Our data suggest that SHP-2 mutations in Noonan syndrome cause mild GH resistance by a postreceptor signaling defect, which seems to be partially compensated for by elevated GH secretion. This defect may contribute to the short stature phenotype in children with SHP-2 mutations and their relatively poor response to rhGH.

Abstract Previous studies have demonstrated the importance of energy metabolism as it relates to numerous aspects of leukemia stem cell (LSC) biology. Specifically, in acute myelogenous leukemia (AML), it has been shown that LSCs have a unique reliance on oxidative phosphorylation (OXPHOS), and that inhibition of B-cell lymphoma 2 (BCL-2) acts to down-regulate OXPHOS and eradicate LSCs in pre-clinical models. In the clinical setting, when BCL-2 inhibitor venetoclax is combined with azacitidine, high response rates (~80%) in elderly de novo AML patients have been observed (PMID: 29339097). Nonetheless, a significant portion of these patients ultimately experience disease progression. The mechanism of resistance and characteristics of these patients is poorly understood. Our preliminary data shows that the venetoclax + azacitidine (ven/aza) regimen targets LSCs through alteration of energy metabolism. Specifically, the regimen disrupts the TCA cycle leading to decreases in ATP production and inhibition of OXPHOS. This metabolic targeting is central to ven/aza efficacy and we hypothesize that resistance and progression of AML patients is due to compensatory mechanisms that restore sufficient levels of OXPHOS (PMID:3333149). Investigation of such mechanisms led us to explore the potential activity of MCL1. Previous studies have shown MCL1 can influence venetoclax resistance, however little is known about MCL1's role in metabolism, although a report in breast cancer cells suggests MCL1 modulates OXPHOS (PMID: 28978427). In leukemia, MCL1 expression has been shown to be partially upregulated through mutations in protein tyrosine phosphatase non- receptor type 11 (PTPN11), and PTPN11 mutations have been shown to increase LSC frequency. Thus, we hypothesized that PTPN11 mutations may confer resistance to venetoclax-based regimens at least partially by up-regulation of MCL1. To test this hypothesis, we investigated the relationship between PTPN11 mutations, MCL1, and the metabolic phenotype. In comparison to specimens with a wild type allele, LSCs isolated from PTPN11 mutant patient specimens showed increased levels of OXPHOS as well as glycolysis, amino acids, and fatty acids, suggesting an ability to utilize multiple energy sources for survival. PTPN11 mutant specimens also show decreased sensitivity to venetoclax, suggesting OXPHOS is not affected by venetoclax to the same degree as PTPN11 wild type specimens (fig. 1). Furthermore, when we introduced a mutated allele of PTPN11 into a primary AML specimen we observed increased oxidative phosphorylation and glycolysis, which correlated with decreased in vitro sensitivity to venetoclax (fig. 2). To test the potential role of MCL1 in PTPN11 mutant specimens, we employed a small molecule MCL-1 inhibitor. Metabolic analysis of specimens treated with the MCL-1 inhibitor showed decreased OXPHOS in PTPN11 mutant specimens (fig 3). Further, PTPN11 mutant specimens exhibit increased sensitivity to the MCL-1 inhibitor (fig. 4). To investigate a potential mechanistic link to clinical observations, we next examined 45 older, previously untreated AML patients from our institution who received ven/aza, both in the context of the multi-institutional study NCT02203773 (N=33) and with off-label use (N=12). Of 12 variables examined, only the presence of PTPN11 predicted shorter response duration (table 1). In addition, of the 9 patients who progressed ven/aza, 2 (22%) acquired PTPN11 mutations upon progression, further suggesting PTPN11 may represent a resistance mechanism to this regimen. Notably, PTPN11 is not preferentially detected in patients who progress after regimens other than ven/aza. In conclusion, AML containing PTPN11 mutations exhibit a unique energy metabolism profile. These specimens also appear to have increased sensitivity to MCL-1 inhibitors. The presence of PTPN11 mutations represents both a novel method for predicting response to ven/aza and a potential strategy for targeting patients who progress. We propose that addition of an MCL-1 inhibitor for treatment of AML patients bearing PTPN11 or related mutations may increase therapeutic responses. Disclosures Savona: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Consultancy. Fesik:Boehringer Ingelheim: Consultancy. Pollyea:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy.

Abstract Background:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, disproportionally affecting African American and Hispanic patients, and germline BRCA1/2 mutation carriers. Prognosis of relapsed, metastatic disease is extremely poor and effective well-tolerated therapies are urgently needed. Our collaborators have discovered that TNBCs often lose feedback control of receptor tyrosine kinases (RTKs) including PDGFR and MET, locking these receptors in a chronically active state. These receptors share a common negative regulator called Protein Tyrosine Phosphatase, Non-Receptor Type 12 (PTPN12). Baylor investigators have shown that PTPN12- deficient TNBCs may be responsive to combined RTK inhibition. Sitravatinib is a spectrum selective RTK inhibitor that has shown strong antitumor activity in patient derived xenografts (PDXs) of TNBC with low levels of PTPN12. We have therefore designed a phase II, multi-institution, two cohort trials to evaluate the efficacy of sitravatinib in patients with metastatic TNBC (mTNBC). Methods: Patients with diagnosis of mTNBC who have received at least one line of chemotherapy +/- atezolizumab for advanced disease would be considered for enrollment. Patients would need to have tissue from metastatic site available for evaluation or agree to undergo biopsy if banked tumor tissue is not available. Sitravatinib at 100 mg daily, the recommended phase 2 dose for sitravatinib monotherapy, will be started at the initiation of the study and continued until progression or unacceptable toxicity. The study will employ a modified optimal Simon’s two stage design. Patients will be recruited into two cohorts: PTPN12 low or PTPN12 high/normal cohorts simultaneously and independently. Seven patients will be enrolled to each arm during the first stage. After the first stage, depending on the observed number of responses, the study will proceed to the 2nd stage. The primary endpoint is progression-free survival status at 24 weeks (PFS24). Current Trial status: The trial is funded by Mirati Therapeutics and opened to enrollment at Dan L Duncan Comprehensive Cancer Center (DLDCCC) clinics as of 6/8/21. Trial is due to open at UT Southwestern Dallas by 11/2021. The correlative science is funded by an institutional SPORE grant. Conclusion: This trial aims to show that sitravatinib is safe and to investigate whether it could be a treatment option in mTNBC. Citation Format: Maryam Nemati Shafaee, Kristen Otte, Nicholas J Neill, Kent C Osborne, Thomas F Westbrook, Susan Hilseneck, Matthew J Ellis. A phase 2 study of sitravatinib in metastatic, pre-treated, triple negative breast cancer, NCT # 04123704 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-28-01.

L'activité fonctionnelle des cellules immunes est régulée par un équilibre entre des signaux activateurs et inhibiteurs. Les récepteurs inhibiteurs KIR (Killer cell Ig-like Receptors) exprimés par les cellules NK et par les lymphocytes T effecteurs mémoires lient les molécules du CMH-I et suppriment l'activation cellulaire via le recrutement de SHP-1. Pour mieux comprendre le rôle des KIR sur les cellules T CD4⁺, des transfectants KIR2DL1 ont été obtenus à partir d'une lignée T Jurkat et de lymphocytes T CD4⁺ primaires. Suite à une stimulation du TCR, la production d'IL-2 est augmentée dans les cellules T CD4⁺ transfectées par le KIR2DL1 indépendamment de son engagement, mais suite à son engagement l'activation induite par le TCR est inhibée. La co-stimulation du signal positif initié par le TCR via le KIR2DL1 nécessite des ITIM intacts et fait suite à leur phosphorylation. Il s'en suit le recrutement de SHP-2 et une augmentation de la phosphorylation de PKCθ et ERK. Lors du contact avec une cellule cible, la synapse est caractérisée par une augmentation du recrutement des p-Tyr, de SHP-2 et de la PKCθ. L'interaction avec une cellule cible exprimant les ligands du KIR2DL1 induit sa forte accumulation à la synapse et le recrutement de SHP-1/SHP-2 qui inhibent la production d'IL-2. Le KIR2DL1 induirait deux signaux opposés dans les cellules T CD4⁺ dépendant ou non de son engagement. Les résultats inattendus observés sur la régulation des cellules T CD4⁺ par le KIR2DL1, de part la dualité fonctionnelle des ITIM est fondamentale pour déterminer la capacité du système immunitaire à développer une réponse appropriée, c'est à dire à maintenir la balance tolérance/immunité
The functional activity of immune cells is controlled by a balance between activators and inhibitors signals. The Inhibitory killer Ig-like receptors (KIR) expressed on NK cells and memory effectors T-cell recognize the CMH-I molecules and inhibit cellular activation by SHP-1 recruitment. To better understand the fonction of KIR receptors on CD4⁺ T-cells, KIR2DL1 transfectants were obtained from human T-cell line and from primary CD4⁺ T-cells. Following TCR stimulation, IL-2 production is increased in CD4+ T cells transfected by KIR2DL1 independently of its engagement. When KIR2DL1 is engaged by its cognate ligand the TCR activation is inhibited. Co-stimulation of the TCR signaling by KIR2DL1 requires intact ITIM and their phosphorylation. It induces a subséquent SHP-2 recruitment and an increased of PKCθ and ERK phosphorylation. Synapses leading to activation are characterized by an increase in the recruitment of p-Tyr, SHP-2, and p-PKCθ. Interaction of KIR2DL1 with its ligand leads to a strong synaptic KIR2DL1 accumulation and SHP-1/SHP-2 recruitment resulting in the inhibition of TCR-induced IL-2 production. These data reveal that KIR2DL1 may induce two opposite signaling outputs in CD4⁺ T cells, depending on whether the KIR receptor is bound to its ligand. The unexpected results observed on the regulation of CD4⁺ T cells by KIR2DL1 receptors, through the functional duality of ITIM, is fundamental to determine the immune System capacity to develop an adapted answer, i. E. To maintain the balance between tolerance and immunity

Deregulierung des RAS/MAPK Signalwegs führen nicht nur zur Krebsentstehung, sondern sind auch mitverantwortlich für Entwicklungsstörungen, dieals Keimbahnmutationen in Schlüsselregulatoren des MAPK Signalwegs zurückzuführen sind, werden aufgrund überlappender Phänotypen unter dem Begriff RASopathien subsumiert. Obwohl die Inzidenz für solide Tumore bei diesen Patienten gering ist, wird ein Zusammenhang zum Auftreten verschiedener Leukämieformen deutlich. Im Rahmen dieser Arbeit wurden Mutationen zweier Schlüsselregulatoren des MAPK Signalwegs, PTPN11 und BRAF, hinsichtlich ihrer Fähigkeit zur neoplastischen Transformation analysiert. Zur Durchführung funktioneller Assays wurden Zelllinien mit lentiviraler Vektoren mit NS-, LS- oder NS und Leukämie-assoziierten SHP2 oder CFC-assoz. BRAF Mutationen (Mut), generiert. Die Testung des neoplastischen Potentials erfolgte anhand nicht-tumorigenen humanen sowie an 208F Ratten-Zelllinie. SHP2/BRAF-Mutationen haben eine spindel-ähnliche Zellmorphologie, Proliferation sowie das Dichte- und Anker-unabhängiges Wachstum in 208F gefördert. Diese Ergebnisse sprechen dafür, dass RASopathie-assoziierte Mutationen zu einem Transformationsphänotyp führen können, ähnlich wie die klassischen Ras Onkogenen. Um zu testen, ob Mut-SHP2 das in vivo Tumorwachstum beeinflusst, wurden SHP2-208F-Zellen in Nacktmäuse injiziert. Eine Förderung des Tumorwachstums konnte sowohl durch mut- als auch durch wt-SHP2 beobachtet werden. RASopathie-assoziierte mutierte Proteine führten auch zu einer moderaten Aktivierung des MAPK-Signalwegs. Eine erhöhte Bindungsstärke zu GAB1 konnte mittels ein TAP-Assay ermittelt werden. Auf transkriptioneller Ebene konnte einer Gensignatur, die sowohl durch RASopathien als auch der klassischen onkogenen BRAF identifiziert werden.Die Ergebnisse dieser Studie können für ein besseres Verständnis der Downstream-liegenden Mechanismen von RASopathie-bezogenen Signalwegen und ihrer Beteiligung an der Tumorprogression beitragen
Deregulation of the Ras/MAPK signaling is implicated in a variety of human diseases, including cancer and developmental disorders. The RASopathies are characterized by an overlapping phenotype in patients and result from germline mutations in key regulators of the MAPK signaling cascade. Although the incidence of solid tumors is rather low, reports on different leukemia forms have increased. In this work, a group of mutations in the genes PTPN11 and BRAF were selected for expression in cell lines for a comprehensive molecular and phenotypic characterization. Non-tumorigenic human cell lines and the rat 208F fibroblasts were transduced with lentiviral particles with SHP2/BRAF wildtype (wt), Noonan (NS)-, NS- and leukemia- or LS–associated SHP2 mutations (mut) and CFC-associated BRAF mutations to identify their potential roles in neoplastic transformation. Mutations in both genes promoted cell morphology alterations, cell proliferation, density- and anchorage-independent growth in rat fibroblasts. These results suggested that RASopathies-associated mutations in both genes confer a transformation phenotype in vitro similar to the classical oncogenes. To investigate whether mutations in SHP2 contribute to tumor growth in vivo, 208F cells expressing wt/mut SHP2 were injected in nude mice. Both wt/mut SHP2 expressing cells promoted tumor growth. Additionally, RASopathies-associated mutant SHP2 and BRAF proteins constitutively activate the MAPK signaling in a moderate manner compared to oncogenic BRAF. To identify modifications in the protein interaction of mut-SHP2, TAP assays were performed. Mut-SHP2 proteins showed an increased binding strength to GAB1 compared to wt. Finally, a microarray analysis revealed a gene cluster commonly regulated in both RASopathies and the oncogenic BRAF. The findings of this work might be useful for a better understanding of the downstream mechanisms of RASopathies-related signaling and their involvement in cancer progression.