Cdc42 Signaling

Cell division cycle 42 (CDC42) acts downstream of cell surface receptors to regulate the formation of different F-actin containing structures and induces the assembly of filopodia. CDC42 regulates a number of polarized responses including actin localization, nuclear displacement, protein trafficking, and directed cell movement. CDC42 is activated by GEF, and repressed by GAP. Major upstream regulators of CDC42 include GPCRs, integrins and RTKs. TCR, upon stimulation, activates CDC42 via ITK followed by Vav2. Vav2 acts as the GEF for CDC42. The molecular mechanism by which GEFs are activated is largely unknown, although it has been shown that Vav family GEFs are directly tyrosine phosphorylated and activated by Src kinase. ACK1 is a binding partner and inhibitor of the GTP-bound form of CDC42; this interaction inhibits both the intrinsic and GAP-stimulated GTPase activity of CDC42.The ability of CDC42 to influence diverse activities stems from its interactions with a large number of kinase and non-kinase effector proteins. Although GTP-bound CDC42 usually interacts with downstream effector proteins containing a conserved binding motif called a CRIB1 domain, some downstream CDC42 effector proteins such as IQGAP do not contain CRIB domains. PAKs, a family of kinase effector proteins, participate in CDC42-mediated cytoskeletal rearrangements that lead to cell motility. They also activate the JNK, ERK and p38 stress kinase pathways. PAK3 activates the ERK pathway while PAK2 and PAK4 activate JNK, which then activates the transcription factors c-Jun and c-Fos. PAK1 activates p38 which phosphorylates several transcription factors including ATF2. Other substrates of PAK include LIMK, which leads to actin polymerization by phosphorylating and inactivating cofilin and MLCK, thus playing an important role in actinomyosin contractility. Other effectors of CDC42 such as MRCK kinases, affect actin/myosin re-organization by phosphorylating non-muscle myosin light chain. WASP and a related protein, N-WASP, comprise a family of non-kinase CRIB containing proteins that function in actin polymerization. Another protein activated by CDC42, MLK kinase, plays a role in kinesin function and JNK activation.Other effectors of CDC42 include IQGAP, TOCA1, PAR-6, DRF3 and RalA. CDC42 binds to IQGAP, which regulates cell-cell adhesion and microtubule orientation. By binding to the microtubule tip protein Clip170, IQGAP1 captures growing microtubules at the leading edge of migrating fibroblasts, which results in cell polarization. CDC42 involved in the dynamics of actin cytoskeleton and cell polarity, binds to a protein complex containing PAR-6, PAR-3/ASIP, and aPKC. TOCA1 is also an essential component of the CDC42 pathway which promotes actin nucleation by activating the N-WASP-WIP/CR16 complex, the predominant form of N-WASP in cells. CDC42 also mediates cell polarity in several systems including migrating cells and early embryos, which involves reorientation of the microtubule organizing center (MTOC) and golgi apparatus toward the direction of movement.