Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IQGAP1 is a key scaffold protein that regulates numerous cellular processes and signaling pathways. Analogous to many other cellular proteins, IQGAP1 undergoes post-translational modifications, including phosphorylation. Nevertheless, very little is known about the specific sites of phosphorylation or the effects on IQGAP1 function. Here, using several approaches, including mass spectrometry, site-directed mutagenesis, siRNA-mediated gene silencing and chemical inhibitors, we identified the specific tyrosine residues that are phosphorylated on IQGAP1 and evaluated the effect on function. Tyr-172, Tyr-654, Tyr-855 and Tyr-1510 were phosphorylated on IQGAP1 when phosphotyrosine phosphatase activity was inhibited in cells. IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src, or siRNA-mediated knockdown of MET. To investigate the biological sequelae of phosphorylation, we generated a non-phosphorylatable IQGAP1 construct by replacing Tyr-1510 with alanine. The ability of hepatocyte growth factor, the ligand for MET, to promote AKT activation and cell migration was significantly greater when IQGAP1-null cells were reconstituted with IQGAP1 Y1510A than when cells were reconstituted with wild-type IQGAP1. Collectively, our data suggest that phosphorylation of Tyr-1510 of IQGAP1 alters cell function. Since increased MET signaling is implicated in the development and progression of several types of carcinoma, IQGAP1 may be a potential therapeutic target in selected malignancies.
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PMID:Tyrosine phosphorylation of the scaffold protein IQGAP1 in the MET pathway alters function. 3308 47

EGFR-TKIs are facing a big challenge of everlasting activated EGFR mutations which lack of effective binding sites, this barrier confers the dark sides that largely limited the outcome of NSCLC patients in clinic. Combination strategies show impressive anti-tumor efficacy comparing with EGFR-TKI mono-treatment, especially targeting both stem cells and non-stem cells. SHP2 (Src homology 2-containing phosphotyrosine phosphatase 2) plays an important role in regulating various malignant biology through hyper-activating intracellular pathways due to either over expression or catalytical mutation. Some pathways that SHP2 involved in were overlaps with EGFR downstream, and others were not subject to EGFR. Interestingly, SHP2 suppression was reported that can destroy the stemness of cancer. Therefore, we hypothesize SHP2 inhibitor might be an promising drug that could synergistically enhance or sensitize the anti-tumor efficacy of EGFR-TKIs in EGFR mutated NSCLC patients. Here, we summarized the mechanisms of SHP2 in regulating EGFR mutated NSCLC patients, attempted to reveal the potential synergistic effects of SHP2 inhibitor combined with EGFR-TKIs.
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PMID:SHP2 Inhibition Benefits Epidermal Growth Factor Receptor mutated Non-Small Cell Lung Cancer Therapy. 3324 69


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