| CDC42 is a small Rho‑family GTPase that acts as a conserved molecular switch controlling actin cytoskeleton organization, cell polarity, membrane trafficking, and signaling pathways that regulate growth and differentiation across diverse mammalian tissues. The protein contains a canonical small GTPase fold with a P‑loop NTP‑binding domain, switch I and II regions that change conformation upon GTP binding and hydrolysis, and a C‑terminal CAAX motif that is prenylated to anchor CDC42 at specific membrane compartments where receptors and scaffolding proteins recruit its dedicated guanine nucleotide exchange factors and GTPase‑activating proteins. CDC42 cycles between GDP‑bound inactive and GTP‑bound active states under the coordinated action of GEFs that catalyze GDP–GTP exchange, GAPs that accelerate intrinsic GTP hydrolysis, and RhoGDIs that bind GDP‑loaded CDC42 and retain it in the cytosol until appropriate signals release it for membrane targeting and activation. Active CDC42 engages multiple effector proteins, including p21‑activated kinases, N‑WASP/WASP, and PAR polarity complexes, and these effectors connect CDC42 activation to Arp2/3‑dependent actin nucleation, formation of actin‑rich filopodia, establishment of apical–basal polarity, and organization of adherens and tight junctions, which coordinates epithelial morphogenesis, directed migration, and lumen and barrier formation. CDC42 also interacts with IQGAP proteins, MRCK kinases, and regulators at the Golgi and plasma membrane to integrate actomyosin contractility with vesicle trafficking and microtubule dynamics, shaping junctional stability, polarized secretion, and organelle positioning. In endocrine tissues, glucose‑stimulated CDC42 activation functions as an early signal in stimulus–secretion coupling for insulin, where CDC42 regulates cortical actin remodeling and recruitment of exocytotic machinery required for the sustained second phase of insulin release. In signaling networks controlling proliferation and survival, CDC42 modulates pathways such as EGFR–mTORC1 and contributes to activation of downstream cascades including MAPK and PI3K, which influence transcriptional programs and cell‑cycle progression. Germline mutations and dysregulated CDC42 activity associate with developmental and autoinflammatory syndromes, while overexpression or hyperactivation in tumors correlates with enhanced motility, invasive behavior, and metastatic dissemination. |
