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)

Tnk1/Kos1 is a non-receptor protein tyrosine kinase implicated in negatively regulating cell growth in a mechanism requiring its intrinsic catalytic activity. Tnk1/Kos1 null mice were created by homologous recombination by deleting the catalytic domain. Both Tnk1(+/-) and Tnk1(-/-) mice develop spontaneous tumors, including lymphomas and carcinomas, at high rates [27% (14 of 52) and 43% (12 of 28), respectively]. Tnk1/Kos1 expression is silenced in tumors that develop in Tnk1(+/-) mice but not in adjacent uninvolved tissue, and silencing occurs in association with Tnk1 promoter hypermethylation. Tissues and murine embryonic fibroblasts derived from Tnk1/Kos1-null mice exhibit proportionally higher levels of basal and epidermal growth factor-stimulated Ras activation that results from increased Ras-guanine exchange factor (GEF) activity. Mechanistically, Tnk1/Kos1 can directly tyrosine phosphorylate growth factor receptor binding protein 2 (Grb2), which promotes disruption of the Grb2-Sos1 complex that mediates growth factor-induced Ras activation, providing dynamic regulation of Ras GEF activity with suppression of Ras. Thus, Tnk1/Kos1 is a tumor suppressor that functions to down-regulate Ras activity.
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PMID:Tnk1/Kos1 knockout mice develop spontaneous tumors. 1897 14

Tnk1/Kos1 is a non-receptor protein tyrosine kinase implicated in negative regulation of cell growth by a mechanism involving inhibition of Ras activation and requiring Tnk1/Kos1's intrinsic catalytic activity. Tnk1/Kos1 null mice were created by homologous recombination by deleting the catalytic domain. Upon aging, both Tnk1+/- and Tnk1-/- mice develop spontaneous tumors, including lymphomas and carcinomas at high rates (i.e. 27%, and 43%, respectively), indicating that Tnk1/Kos1 is a tumor suppressor. Tissues from Tnk1/Kos1-null mice exhibit proportionally higher levels of basal and growth factor-stimulated Ras activation. Mechanistically, Tnk1/Kos1 requires either or both Y277 and Y287 sites to be intact for enzymatic activity and phosphorylation of its substrate, growth factor receptor binding protein 2 (Grb2). Data indicate that following tyrosine phosphorylation of Grb2 by Tnk1/Kos1, the Grb2-Sos1 guanine exchange factor (GEF) complex that mediates growth factor stimulated Ras activation becomes disrupted, resulting in the reversal of Ras activation. Conversely, the loss of Tnk1/Kos1 activity results in constitutive activation of Ras due to prolonged stabilization/activation of the Grb2-Sos1 GEF activity. Tnk1/Kos1 is the first tyrosine kinase discovered to have tumor suppressor activity, and the mechanism of spontaneous tumor formation involves constitutive, indirect activation of Ras. Thus, Ras may display "oncogenic activity" without undergoing "oncogenic" mutation. We now find that a cohort of patients with diffuse large B-cell lymphoma (DLBCL) display downregulation of Tnk1/Kos1 that may account for tumorigenesis in humans.
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PMID:Tnk1/Kos1: a novel tumor suppressor. 2069 68

Gab proteins, Grb2 (growth factor receptor binding protein 2)-associated binder, are important scaffolding adapter proteins required by many signaling pathways. In mammals, the Gab proteins mainly consist of Gab1, Gab2 and Gab3, and are involved in the amplification and integration of signal transduction evoked by a variety of extracellular stimuli, including various growth factors and cytokines. They are known to play key roles in many biological processes through the two classical signal pathways, SHP2/RAS/ERK and PI3K/AKT. In this review, we provide an overview of the structure and function of the scaffolding adapter, Gab, with a special focus on its role in tumor, inflammation and cardiovascular diseases.
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PMID:[Structure and function of the adapter protein Gab and its role in the development of tumor, inflammation and cardiovascular diseases]. 2691 23


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