{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPTK2, which encodes focal adhesion kinase (FAK), is a central non‐receptor tyrosine kinase that integrates signals from integrins and growth factors to orchestrate cell adhesion, cytoskeletal reorganization, and mechanotransduction. FAK localizes to focal adhesions where its autophosphorylation (notably at Tyr397) triggers assembly of multi‐protein complexes that include adaptor proteins such as talin and paxillin, thereby regulating the dynamics of adhesion turnover, Rho family GTPase activity, and the generation of integrin‐mediated cellular forces. These studies also show that FAK activity is essential for directing processes as diverse as ECM-induced osteogenic differentiation and the regulation of myofibroblast differentiation by TGF‑β, emphasizing its role in converting extracellular mechanical and biochemical cues into intracellular responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn pathologic settings such as cancer and fibrosis, FAK’s aberrant activation contributes to tumor initiation, progression, and metastasis via multiple mechanisms. FAK facilitates escape from apoptosis by promoting PI3K/Akt signaling and, through its nuclear scaffolding functions, enhances Mdm2-mediated turnover of p53. It also modulates invadopodia dynamics, aids in the maintenance of an invasive phenotype (partly by controlling MT1‑MMP cell surface retention), and feeds into oncogenic cascades involving YAP, ERK, and other effectors. Moreover, FAK is instrumental in the epithelial-to-mesenchymal transition induced by TGF‑β, in the mechanosensitive remodeling of the tumor microenvironment, and in the mediation of survival signals that underlie resistance to chemotherapy and radiotherapy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFAK further impacts vascular and matrix biology by modulating endothelial responses and angiogenesis. Its activation is pivotal for VEGF‐ and neuropilin‑dependent signaling in endothelial cells, influencing focal adhesion assembly and tight junction integrity. FAK localization to endosomal platforms also supports integrin signaling events that contribute to anoikis resistance and metastatic dissemination. The therapeutic inhibition of FAK—with agents that disrupt its kinase activity or scaffolding functions—has shown promise in preclinical models for sensitizing tumors to chemotherapy, preventing metastatic cell adhesion, and mitigating fibrosis-related pathologies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "36", "end_ref": "45"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hiroki Chikumi, Shigetomo Fukuhara, J Silvio Gutkind "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of G protein-linked guanine nucleotide exchange factors for Rho, PDZ-RhoGEF, and LARG by tyrosine phosphorylation: evidence of a role for focal adhesion kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M108504200"}], "href": "https://doi.org/10.1074/jbc.M108504200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11799111"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11799111"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Bin Tian, Khashayar Lessan, Judy Kahm, et al. 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