CDC42 Pathway
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CDC42 Pathway
Dynamic rearrangements of the cytoskeleton and cell adhesion are required for various cellular processes, such as shape changes, migration, and cytokinesis. These temporal and spatial reorganizations of cell structure and cell contacts can be stimulated by extracellular signals, including growth factors, Hormones, Integrins, G-Proteins and other biologically active substances. To achieve strong adhesion to their neighbors and sustain stress and tension, epithelial cells develop many different specialized adhesive structures. Breakdown of these structures occurs during tumor progression with the development of a fibroblastic morphology characteristic of metastatic cells. Adhesion receptors of the Cadherin family have been implicated in these cellular processes, which play an important role in the development and maintenance of the differentiated epithelial phenotype during organogenesis and adult life. Cadherin-mediated adhesion requires the activity of the cytosolic proteins of the Rho subfamily members, Rho , Rac, and CDC42 (Cell Division Cycle-42). They belong to the Ras superfamily of small GTPases, whose function is regulated depending on the type of guanine nucleotide bound (Ref.1).

CDC42 is a member of the p21 Rho family of small GTPases that act downstream of cell surface receptors to regulate the formation of different F-actin-containing structures. It regulates actin polymerization to induce the assembly of filopodia, which are thin actin filaments that project from cells. In mammalian cells, CDC42 regulates a number of polarized responses, including Actin localization, nuclear displacement, and protein trafficking, and directed cell movement. CDC42 is activated by GEF (Guanine Nucleotide Exchange Factors), and repressed by GAPs (GTPase- Activating Proteins). Major upstream regulators of CDC42 include GPCR (G-Protein Coupled Receptor), Integrins and RTKs (Receptor Tyrosine Kinases). GPCRs activate CDC42 using G-Protein , G-Alpha12. G-Alpha12, on activation activates FGD1/3 (FYVE, RhoGEF and PH Domain containing-1/3) which further activates CDC42. TCR (T-Cell Receptor), a complex of integral membrane proteins that participates in the activation of T-Cells in response to the presentation of antigen, also activates CDC42. Stimulation of TCR is triggered by MHC (Major Histocompatibility Complex) molecules on Antigen Presenting Cells that present antigen peptides to TCR complexes and induce a series of intracellular signaling cascades. Stimulated TCR then activates CDC42 via ITK (IL-2 inducible T-cell Kinase) and Vav2 (Oncogene Vav2) respectively.E-Cadherin also activates CDC42 by activating Vav1 (Oncogene Vav1). Vav acts as the GEF for CDC42. The molecular mechanism by which GEF are activated is largely unknown, although it has been known that Vav family GEFs are directly tyrosine-phosphorylated and activated by Src kinase. ACK1 (Activated CDC42-Associated Kinase-1) is recently been identified as a binding partner and inhibitor of the GTP-bound form of CDC42. Interaction between GTP-CDC42 and ACK1 inhibited both the intrinsic and GAP-stimulated GTPase activity of CDC42. Activated CDC42 binds to and specifically activate downstream effectors (Ref.2, 3 & 4).

The ability of CDC42 to influence diverse activities stems from its interactions with a large number of different kinase and non-kinase effector proteins. Although GTP-bound CDC42 usually interacts with downstream effector proteins containing the conserved binding motif called a CRIB1 domain, some downstream CDC42 effector proteins such as IQGAP do not contain CRIB domains. To date, six distinct families of CRIB domain-containing CDC42 effector proteins have been identified: PAK(p21/CDC42/Rac1-Activated Kinase), MRCK (Myotonic Dystrophy Kinase-Related CDC42-Binding Kinase), ACK, MLK (Mixed-Lineage Kinase), WASP (Wiskott-Aldrich Syndrome Protein) and BORG5/MSE55 (Binder of Rho GTPases)/CEP (CDC42 Effector Protein). The first four of these families are Kinases. The most extensively studied CDC42 effector proteins, the PAK Kinases, participate in the CDC42-mediated cytoskeleton rearrangements that lead to cell motility. PAK Kinases also activate the JNK (c-Jun Kinase), ERK (Extracellular Signal-Regulated Kinase) and p38 Stress Kinase pathways and are targets of Caspase-mediated proteolytic cleavage during apoptosis. PAK3 activates ERK Pathway by activating c-Raf. On the other hand PAK2 and PAK4 activates JNKs, which further activates the transcription factors c-Jun and c-Fos. PAK1 activates p38 which phosphorylates several transcription factors includingATF2 (Activating Transcription Factor-2). Other substrates of PAK include LIMK (LIM Kinase), which leads to Actin polymerization by phosphorylating and inactivating Cofilin; OP18 (Oncoprotein-18)/Stathmin, which stabilizes microtubule plus ends; and MLCK (Myosin Light Polypeptide Kinase), which further activates MLC (Myosine Light Chain), which lead to inactivation of Myosin PPtase (Myosin Phosphatase), thus playing an important role in Actomyosin Contractility (Ref.5 & 6). Other effectors of CDC42 like MRCK Kinases, affect actin/myosin reorganization by phosphorylating non-muscle myosin light chain. Less is known about the signaling pathways and cellular processes affected by ACK tyrosine Kinases, but they may influence cell adhesion signals. The fourth family activated by CDC42, MLK kinases, plays a role in kinesin function and JNK activation. WASP and a related protein, N-WASP (Neural Wiskott-Aldrich Syndrome Protein), comprise a family of non-kinase CRIB-containing proteins that function in actin polymerization. N-WASP regulates filopodia formation by producing free actin filaments either via its Cofilin actin-severing domain or through interactions with the Actin-severing protein, Profilin. Both WASP and N-WASP also positively regulate the ARP2/3 (Actin-Related Protein-2/3) protein complex, which stimulates Actin nucleation. The other non-kinase, CRIB-containing set of CDC42 effector proteins, is the MSE55/CEP/BORG family, which is the most structurally diverse (Ref.7, 8 & 9).

Other effectors of CDC42 include IQGAP, TOCA1 (Transducer of CDC42-dependent Actin assembly-1), PAR-6, DRF3 (Diaphanous Related Formin-3) and RalA. CDC42 binds to the actin-binding protein IQGAP, which is implicated in regulation of 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. Recent findings show that CDC42, involved in the dynamics of Actin cytoskeleton and cell polarity, binds to a protein complex containing PAR-6, PAR-3/ASIP, and aPKCs (atypical Protein Kinase-C). TOCA1 (Transducer of CDC42-dependent Actin Assembly) is also an essential component of the CDC42 pathway. TOCA1 binds both N-WASP and CDC42 and is a member of the evolutionarily conserved PCH protein family. TOCA1 promotes actin nucleation by activating the N-WASP-WIP/CR16 complex, the predominant form of N-WASP in cells. Recently, a novel family of CDC42 effector proteins has been identified, that may play a role in this higher level of coordination. This new family, designated SPEC (Small Protein Effector of CDC42) has two human members, SPEC1 and SPEC2. Both are very small and are highly conserved. SPEC1 blocks CDC42-induced JNK activity. Signaling pathways that are regulated by Rho family members play an important role in several pathological conditions, including cancer, inflammation, and bacterial infections. CDC42 mediates cell polarity in several systems including migrating cells and early embryos, which involves reorientation of the MTOC (Microtubule Organizing Center) and Golgi apparatus toward the direction of movement. CDC42 is a regulator for multiple aspects of dendritic morphogenesis (Ref.1, 10, 11& 12).