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GAPs Specific for the rap1/Krev-1 Protein
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
It is perplexing that two such functionally homologous proteins, ras-GAP and rap1-GAP, having reactivities toward two such structurally homologous substrates, p21ras and p21rap1, do not bear any resemblance to each other at the level of primary structure. Conserved sequences thought to be required for rasGAP catalytic activity26 cannot be found in rap1-GAP. The src homology domains, known to be important for the association of ras-GAP with growth factor receptors27 and other tyrosine-phosphorylated proteins,28 are also absent in rap1GAP. Considering this, the two GAPs appear to have little in common outside of their ability to act as signaling terminators for their respective substrates. Yet the apparently opposing biological activities of the ras and rapi proteins, along with the ability of p21rap1 to bind ras-GAP, implies an intracellular network involving the coordinated regulation of these two GAPs. Expression studies indicate that rap1-GAP may be involved in the programming of cell growth and division.13ras-GAP is certainly involved in these processes. As the signaling networks become more clearly delineated we may ultimately discover the intersection connecting the GAPs.
BCR-ABL as a Molecular Target
Published in Jorge Cortes, Michael Deininger, Chronic Myeloid Leukemia, 2006
Abl (also referred to as Abl-1), the human homologue of the Abelson murine leukemia virus, is a tyrosine kinase involved in multiple cellular processes, including DNA repair, integrin signaling, cell cycle regulation, and signal transduction from cell surface receptors (11). ABL knockout mice exhibit increased neonatal lethality and suffer from a number of defects, including skeletal malformations, immune dysfunction as well as an ill-defined wasting syndrome (12,13). Apart from the unique “Cap” region at its very 5’ end the N-terminus of Abl has extensive homology to Src kinases (14). The Src homology domains 3 (SH3) and 2 (SH2) mediate interactions with other proteins by binding proline rich regions (SH3) or phosphotyrosine (SH2). The SH1 domain carries the tyrosine kinase function. The large C-terminus is unique to Abl and contains DNA binding, nuclear localization, and export signals as well as actin-binding sequences and a proline rich domain(15). In physiological conditions, Abl kinase is tightly regulated by a mechanism that is similar as in Src kinases but uses different structures, as Abl lacks a C-terminal tyrosine that is critical for auto-inhibition of Src kinases (14). In Src, phosphorylation of tyrosine 527 allows the N-terminus to form an intramolecular association with the SH2 domain, inactivating the kinase by forcing the molecule into a “clamp.” In Abl, the myristoylated cap binds to a hydrophobic pocket at the base of the kinase domain, resulting in a conformation resembling inactive SRC.
Identification of imidazo[4,5-c]pyridin-2-one derivatives as novel Src family kinase inhibitors against glioblastoma
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Lishun Zhang, Zichao Yang, Huiting Sang, Ying Jiang, Mingfeng Zhou, Chuan Huang, Chunhui Huang, Xiaoyun Wu, Tingting Zhang, Xingmei Zhang, Shanhe Wan, Jiajie Zhang
Src family kinases (SFKs) are a group of non-receptor tyrosine kinases composed of 11 members, including eight main members, such as c-Src (Src), Fyn, Yes, Fgr, Lyn, Blk, Hck, and Lck7,8. They share a set of conserved domains which includes an N-terminal Src homology domain (SH4), followed by a unique domain, two Src homology domains (SH3 and SH2), a catalytic kinase domain (SH1), and a C-terminal regulatory tail9. SFKs are highly expressed in GBM cell lines and tumour samples, in which abnormal activation of SFKs induced multiple tumour-promoting effects, including reducing cell apoptosis, increasing angiogenesis, promoting cell proliferation, motility as well as invasion10–12. In detail, Yes and phosphatidylinositol 3-kinase bind prototypical death receptor CD95 to mediate invasion of GBM13. Hck stimulates GBM progression via mediating epithelial-mesenchymal transition process14. Lyn enhances GBM cell survival by promoting autophagy under nutrient deprivation15. More importantly, both Src and Fyn are downstream targets of EGFR oncogenic signalling, and their overexpression is frequently occurred in GBM patients. Glioblastoma exhibiting activated EGFR signalling also showed the activation of Src and Fyn, which indicates that Src and Fyn inhibition may improve the efficacy of anti-EGFR targeted therapy16–18.
Is neurotrophin-3 (NT-3): a potential therapeutic target for depression and anxiety?
Published in Expert Opinion on Therapeutic Targets, 2020
A. S. de Miranda, J. L. V. M. de Barros, Antonio Lucio Teixeira
BDNF and its high-affinity receptor TrkB are widely expressed throughout the adult brain, including cortex, hippocampus, multiple brainstem, and spinal cord nuclei [45]. The transmembrane TrkB dimerization and autophosphorylation in response to BDNF ligand lead to activation of adaptor proteins like polypyrimidine tract-binding protein (PTB) and Src homology domain 2 (SH2), resulting in the phosphorylation of PI3K, MAPK–ERK, phospholipase Cγ1 (PLCγ1), and CREB (cAMP-response element-binding protein) signaling pathways [12,46]. These pathways are implicated in several biological actions of BDNF, such as sustaining neurite outgrowth, cellular differentiation, and neuronal survival during development while modulating dendritic branching, dendritic spine morphology, neurogenesis, synaptic plasticity, and LTP in the adult brain [47].
An evaluation of zanubrutinib, a BTK inhibitor, for the treatment of chronic lymphocytic leukemia
Published in Expert Review of Hematology, 2020
Praveen Ramakrishnan Geethakumari, Farrukh Awan
BTK is one of the five members of the TEC family of non-receptor tyrosine kinases; along with TEC (tyrosine kinase expressed in hepatocellular carcinoma), interleukin-2 inducible T-cell kinase (ITK), resting lymphocyte kinase (RLK) and bone marrow tyrosine kinase on chromosome X (BMX). BTK, TEC, and ITK are structurally very similar and contain five different protein interaction domains [amino terminal pleckstrin homology (PH), TEC-homology (TH), SRC homology domains SH2 and SH3, and the kinase domain with enzymatic activity]. BTK is cytoplasmic and is recruited to the membrane through interaction of the PH-domain phosphatidyl inositol-3,4,5-triphosphate (PIP3) that is generated by phosphatidylinositol-3 kinase (PI3K). BTK activation occurs through two steps; phosphorylation at position Y551 in the kinase domain by SYK or SRC kinases and subsequent auto phosphorylation at position Y223 in the SH3 domain [9,11,12].