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Small-Molecule Inhibitors Targeting Receptor Tyrosine Kinases in Cancer
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Mohammad Hojjat-Farsangi, Gholamreza Khamisipour
The extracellular region or RTKs is preceded by a cleavable signal sequence. This region provides the binding site for ligand/s and is involved in RTKs dimerization that may be important for the activation of intrinsic tyrosine kinase (TK) region (Hubbard and Till, 2000; Watson, 1984; Ostman and Bohmer, 2001). The kinase domain of RTKs is located in cytoplasmic part and contains tyrosine amino acids that are phosphorylated following the binding of ligand to extracellular region and results in activation of downstream molecules, regulation of catalytic function and also may serves as a docking site for proteins with SRC Homology 2 (SH2) domain/s (Hubbard, 1999).
Skeletal Mechanobiology
Published in Jiro Nagatomi, Eno Essien Ebong, Mechanobiology Handbook, 2018
Alesha B. Castillo, Christopher R. Jacobs
As integrins do not possess intrinsic catalytic activity, ECM-intracellular signal transduction is carried out by activation of downstream signaling molecules comprising focal adhesions. FAK, a nonreceptor tyrosine kinase,188 is one of the first molecules recruited to focal adhesions upon integrin binding189 and has been shown to be important in cell migration, proliferation, and survival. FAK has also been implicated in cellular mechanotransduction,190,191 including bone cells.192–194 The activation of FAK results in the autophosphorylation of tyrosine 397 creating a high-affinity binding site for the Src-homology 2 (SH2) domain195 of the Src family protein tyrosine kinases. FAK and SH2 binding activates MAPK signaling196 though interaction with c-src, Grb2, and the small GTPase Ras.197,198 Fluid flow leads to FAK phosphorylation199 and MAPK activation in bone and endothelial cells.200,201 FAK phosphorylation has also been linked to NFκB activation202 as well as calcium release via large conductance calcium channels.203 Disruption of FAK in osteoblasts leads to decreases in the fluid flow-induced ERK phosphorylation, expression of c-fos and Cox-2, as well as PGE-2 release,194 all of which are important signaling events in osteoblast function. Interestingly, preliminary data suggest that osteocyte-specific gene ablation of FAK does not affect load-induced cortical bone formation in vivo (unpublished data). Thus, FAK appears to play a lesser role in the sensing of and response to fluid flow in osteocytes in vivo, and a more prominent role in downstream bone formation events, such as osteoblast differentiation and recruitment. Indeed, the disruption of FAK in osteoblasts abolishes the response of bone marrow cells to mechanical stimuli in a tibial injury model204 indicating a potential role for FAK in osteoprogenitor recruitment and homing. Recent data suggest that proline-rich tyrosine kinase 2 (Pyk2) may compensate for loss of FAK in various cell types including endothelial cells205 and fibroblasts.206 However, Pyk2 expression was not enhanced in FAK−/− osteoblasts,194 and it is unclear whether Pyk2 has a compensatory effect on load-induced bone formation in vivo. In fact, Pyk2 null mice exhibit increased bone mass and bone formation suggesting that Pyk2 normally represses osteoblast differentiation.207
Residue-specific free energy analysis in ligand bindings to JAK2
Published in Molecular Physics, 2018
Yifan Zhou, Xiao Liu, Youzhi Zhang, Long Peng, John Z. H. Zhang
Janus kinase (JAK), a type of intracellular, non-receptor tyrosine kinases family, is extensively expressed in diverse cells and can transmit extra-cellar signals via the JAK-STAT pathway. JAK plays prominent roles in cell proliferation, differentiation, immunity, and apoptosis [1,2]. The JAK family has four members: JAK1, JAK2, JAK3 and TYK2 [3–5]; among them, JAK2 is mainly activated in response to cytokine, such as interleukin, prolactin and growth hormone [6]. The activated JAKs phosphorylate tyrosine residues on the receptor subsequently, and therefore the phosphorylated tyrosine residues with neighbouring residues can form a ‘docking site’ for STATs, so that the SH2 domain containing STATs are recruited to the corresponding receptor and immediately tyrosine-phosphorylated by JAKs. Although there are seven STATs (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6), STAT3 and STAT5 are the preferred downstream targets of phosphorylated JAK2 [5,7]. The phosphorylated STATs dissociate from the receptor, and then translocate to the nucleus, where they can play a vital role that influences DNA transcription as well as in the regulation of the gene expression [2,7–10].