{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPLEKHG2, a Dbl family guanine nucleotide exchange factor, primarily activates the Rho family GTPases Rac and Cdc42 in response to upstream signals such as heterotrimeric G protein βγ subunits. Through this activation, PLEKHG2 promotes actin cytoskeletal reorganization, enhances serum response element (SRE)‐dependent gene transcription, and facilitates cellular processes including cell spreading and membrane protrusion formation. Its paralog Clg has also been shown to specifically activate Cdc42 in oncogenic contexts, highlighting a conserved role in modulating small GTPase signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPLEKHG2 activity is intricately regulated by multiple mechanisms. Its function can be modulated by direct interactions with binding partners such as non‐muscle cytosolic actin—which negatively influences its SRE‐dependent transcriptional output—and by its pleckstrin homology (PH) domain that mediates membrane targeting through binding to polyphosphoinositides. Furthermore, post‐translational modifications are pivotal; tyrosine phosphorylation by cSrc at Tyr489 and by the Ras/MAPK pathway (following EGFR transactivation) at Thr680 enhances or modulates its activity, while binding of the active Gαs subunit directly masks its catalytic DH domain, thereby attenuating its function. In addition, distinct isoforms of the LIM domain protein FHL1 interact with PLEKHG2 to enhance its signaling output."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinical and cellular studies further underscore the importance of precise PLEKHG2 regulation. For example, a mutation (Arg204Trp) in PLEKHG2 that markedly reduces its basal and stimulated activity impairs actin polymerization and lymphocyte migration, thereby linking its dysfunction to developmental disorders such as mental retardation and dystonia. Collectively, these findings indicate that PLEKHG2 functions as a signal integrator that couples extracellular cues to Rac/Cdc42‐mediated cytoskeletal dynamics and gene transcription—a role fundamental to normal cell morphology, motility, and immune cell chemotaxis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Karen L Himmel, Feng Bi, Haifa Shen, et al. 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