{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CRK is a versatile adaptor protein that functions as a central integrator of signaling pathways regulating cell adhesion, migration, proliferation, and differentiation in both normal physiology and disease. Viral oncogenes such as p47gag‐CRK can activate endogenous tyrosine kinases to drive transformation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In cancer cells, elevated CRK levels are associated with increased tumor invasiveness, whereas microRNA‐126–mediated downregulation of CRK results in reduced cell adhesion, migration, and invasion in lung and gastric cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In developmental contexts, the CRK family member CRKL is crucial for the proper function, differentiation, and/or survival of neural crest cells; loss‐of‐function mutations in CRKL recapitulate multiple congenital defects observed in DiGeorge/velocardiofacial syndrome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n CRK proteins also mediate cytoskeletal reorganization. For example, they participate in multiprotein complexes—often via p130Cas and Dock180—that activate Rac1 to regulate events such as lamellipodia formation in phagocytosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "and to promote motility and invasion in response to epidermal growth factor receptor signaling via Brk-induced paxillin phosphorylation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In neurons, CRK and its paralogue CRKL are integral to Reelin-mediated signaling: following Dab1 phosphorylation, the formation of Dab1–CRK/CRKL complexes triggers downstream effectors—including C3G, Akt, and Rap1—to promote integrin activation, terminal translocation, and proper neuronal layering."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, bacterial pathogens can target CRK to subvert host defenses. For example, the ADP-ribosylation activity of Pseudomonas aeruginosa ExoT specifically modifies Crk proteins—thereby impairing downstream signaling involved in phagocytosis—which contributes to the anti-internalization phenotype during infection."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore that CRK proteins act as key nodal adaptors integrating diverse extracellular cues—from growth factors and extracellular matrix engagement to microbial virulence factors—and translating them into coordinated intracellular responses critical for normal development, metabolic regulation, and cancer progression.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "B J Mayer, M Hamaguchi, H Hanafusa "}, {"type": "b", "children": [{"type": "t", "text": "A novel viral oncogene with structural similarity to phospholipase C."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (1988)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/332272a0"}], "href": "https://doi.org/10.1038/332272a0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "2450282"}], "href": "https://pubmed.ncbi.nlm.nih.gov/2450282"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Runhua Feng, Xuehua Chen, Yingyan Yu, et al. 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