Signaling role of Cdc42 in regulating mammalian physiology

Abstract

Cdc42 is a member of the Rho GTPase family of intracellular molecular switches regulating multiple signaling pathways involved in actomyosin organization and cell proliferation. Knowledge of its signaling function in mammalian cells came mostly from studies using the dominant-negative or constitutively active mutant overexpression approach in the past 2 decades. Such an approach imposes a number of experimental limitations related to specificity, dosage, and/or clonal variability. Recent studies by conditional gene targeting of cdc42 in mice have revealed its tissue- and cell type-specific role and provide definitive information of the physiological signaling functions of Cdc42 in vivo.

FIGURE 1.

Conventional view of the signaling function and regulation of Cdc42. Cdc42 cycles between the GDP-bound inactive state and the GTP-bound active state. The GTP binding and GTP hydrolysis cycle is tightly regulated at specific intracellular locations by GEFs, GAPs, and GDIs. Upon activation by various stimuli, activated Cdc42 can transiently interact with multiple effector proteins to transduce signals that impact on cell functions, including cytoskeleton organization, vesicle trafficking, cell cycle progression, survival, translation, and transcription.

FIGURE 2.

Examples of the signaling role of Cdc42 in selective tissue cell types. A, Cdc42 controls pancreatic progenitor cell polarity and the formation of apical lumens that ultimately combine to form tubules during pancreatic development (adapted from Ref. 42). Ptd Ins, phosphatidylinositol. B, Cdc42 regulates multiple neuronal cell functions. Through the Par3-Par6-aPKC complex, Cdc42 controls neural epithelial progenitor polarity. The PAK-mediated cofilin pathway and N-WASP-mediated Arp2/3 pathway may counterbalance the dynamic actin structures required for neuronal migration and axonal expansion. LIMK, LIM kinase. C, Cdc42 coordinates the survival signal from the IL-7 receptor (IL7R) and the proliferative signal from the T cell receptor (TCR) in regulating naive T cell homeostasis. D, Cdc42 integrates M-CSF- and RANKL-induced osteoclastogenic signals to regulate osteoclast proliferation, survival, and bone resorption.