Optimization of Phosphotyrosine Peptides that Target the SH2 Domain of SOCS1 and Block Substrate Ubiquitination

2022 ◽  
Author(s):  
Hao Chen ◽  
Yuntong Wu ◽  
Kunlun Li ◽  
Iain Currie ◽  
Narelle Keating ◽  
...  
Keyword(s):  
Sh2 Domain

SHCA PHOSPHOTYROSINE DERIVED SIGNALING IS REQUIRED FOR THE MAINTENANCE OF CARDIAC FUNCTION

2008 ◽  
Vol 31 (4) ◽  
pp. 23
Author(s):  
Rachel Vanderlaan ◽  
Rod Hardy ◽  
Golam Kabir ◽  
Peter Back ◽  
A J Pawson
Keyword(s):  
Extracellular Matrix ◽  
Cardiac Function ◽  
Tyrosine Kinases ◽  
Sh2 Domain ◽  
Scaffolding Protein ◽  
Restricted Domain ◽  
Downstream Signaling ◽  
Matrix Interactions ◽  
Extracellular Matrix Interactions ◽  
Ptb Domain

Background: ShcA, a scaffolding protein, generates signalspecificity by docking to activated tyrosine kinases through distinct phosphotyrosine recognition motifs, while mediating signal complexity through formation of diverse downstream phosphotyrosine complexes. Mammalian ShcA encodes 3 isoforms having a modular architecture of a PTB domain and SH2 domain, separated by a CH1 region containing tyrosine phosphorylation sites important in Ras-MAPK activation. Objective and Methods: ShcA has a necessary role in cardiovascular development^1,2. However, the role of ShcA in the adult myocardium is largely unknown, also unclear, is how ShcA uses its signaling modules to mediate downstream signaling. To this end, cre/loxP technology was employed to generate a conditional ShcA allele series. The myocardial specific ShcA KO (ShcA CKO) and myocardial restricted domain mutant KI mice were generated using cre expressed from the mlc2v locus^3 coupled with the ShcA floxed allele and in combination with the individual ShcA domain mutant KI alleles^2. Results: ShcACKO mice develop a dilated cardiomyopathy phenotype by 3 months of life, typified by depressed cardiac function and enlarged chamber dimensions. Isolated cardiomyocytes from ShcA CKO mice have preserved contractility indicating an uncoupling between global heart function and single myocyte contractile mechanics. Force-length experiments suggest that the loss of shcAmediates the uncoupling through deregulation of extracellular matrix interactions. Subsequent, analysis of the ShcA myocardial restricted domain mutant KImice suggests that ShcA requires PTB domain docking to upstream tyrosine kinases and subsequent phosphorylation of the CH1 tyrosines important for downstream signaling. Conclusion: ShcA is required for proper maintenance of cardiac function, possibly regulation of extracellular matrix interactions. References: 1. Lai KV, Pawson AJ. The ShcA phosphotyrosine docking protein sensitizescardiovascular signaling in the mouse embryo. Genes and Dev 2000;14:1132-45. 2. Hardy WR. et al. Combinatorial ShcA docking interactions supportdiversity in tissue morphogenesis. Science2007;317:251-6. 3.Minamisawa, s. et al. A post-transcriptional compensatory pathway inheterozygous ventricular myosin light chain 2-deficient mice results in lack ofgene dosage effect during normal cardiac growth or hypertrophy. J Biol Chem 1999;274:10066-70.

Design Potential Selective Inhibitors for Treating Cancer by Targeting the Src Homology 2 (SH2) Domain-Containing Phosphatase 2 (Shp2) with Core Hopping Approach

2014 ◽  
Vol 21 (6) ◽  
pp. 556-563 ◽  
Author(s):  
Yu-Qing Duan ◽  
Ying Ma ◽  
Xue-Jiao Wang ◽  
Yuan-Yuan Jin ◽  
Run-Ling Wang ◽  
...  
Keyword(s):  
Sh2 Domain ◽  
Selective Inhibitors ◽  
Src Homology 2 ◽  
Src Homology

scholarly journals Localization of the insulin receptor binding sites for the SH2 domain proteins p85, Syp, and GAP.

1994 ◽  
Vol 269 (44) ◽  
pp. 27186-27192
Author(s):  
P A Staubs ◽  
D R Reichart ◽  
A R Saltiel ◽  
K L Milarski ◽  
H Maegawa ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Receptor Binding ◽  
Binding Sites ◽  
Sh2 Domain ◽  
Insulin Receptor Binding

scholarly journals SHIP1, an SH2 Domain Containing Polyinositol-5-phosphatase, Regulates Migration through Two Critical Tyrosine Residues and Forms a Novel Signaling Complex with DOK1 and CRKL

2000 ◽  
Vol 276 (4) ◽  
pp. 2451-2458 ◽  
Author(s):  
Martin Sattler ◽  
Shalini Verma ◽  
Yuri B. Pride ◽  
Ravi Salgia ◽  
Larry R. Rohrschneider ◽  
...  
Keyword(s):  
Sh2 Domain ◽  
Tyrosine Residues ◽  
Signaling Complex

scholarly journals The Relevance of the SH2 Domain for c-Src Functionality in Triple-Negative Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 462
Author(s):  
Víctor Mayoral-Varo ◽  
María Pilar Sánchez-Bailón ◽  
Annarica Calcabrini ◽  
Marta García-Hernández ◽  
Valerio Frezza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Sh2 Domain ◽  
Model Systems ◽  
System A ◽  
Promising Therapeutic Target ◽  
Relevant Role ◽  
Inactivating Mutation

The role of Src family kinases (SFKs) in human tumors has been always associated with tyrosine kinase activity and much less attention has been given to the SH2 and SH3 adapter domains. Here, we studied the role of the c-Src-SH2 domain in triple-negative breast cancer (TNBC). To this end, SUM159PT and MDA-MB-231 human cell lines were employed as model systems. These cells conditionally expressed, under tetracycline control (Tet-On system), a c-Src variant with point-inactivating mutation of the SH2 adapter domain (R175L). The expression of this mutant reduced the self-renewal capability of the enriched population of breast cancer stem cells (BCSCs), demonstrating the importance of the SH2 adapter domain of c-Src in the mammary gland carcinogenesis. In addition, the analysis of anchorage-independent growth, proliferation, migration, and invasiveness, all processes associated with tumorigenesis, showed that the SH2 domain of c-Src plays a very relevant role in their regulation. Furthermore, the transfection of two different aptamers directed to SH2-c-Src in both SUM159PT and MDA-MB-231 cells induced inhibition of their proliferation, migration, and invasiveness, strengthening the hypothesis that this domain is highly involved in TNBC tumorigenesis. Therefore, the SH2 domain of c-Src could be a promising therapeutic target and combined treatments with inhibitors of c-Src kinase enzymatic activity may represent a new therapeutic strategy for patients with TNBC, whose prognosis is currently very negative.

Sign in / Sign up

Export Citation Format

Share Document