Actin Cytoskeleton Signaling

The actin cytoskeleton plays an important role in dynamic processes such as cell motility, axon guidance, cytokinesis and phagocytosis. Cell movements are the result of adhesion, loss of attachment and successive re-adhesion of filopodia and lamellipodia. These cellular remodeling requires precise regulation of actin filament assembly/disassembly and organization. Multiple signaling pathways control the rearrangements of the actin cytoskeleton. Members of the Rho family of small GTPases, including RhoA, Cdc42 and Rac, are activated by various classes of transmembrane receptors, such as Integrin receptors, Receptor tyrosine kinase, G protein-coupled receptors, and transmit signals to their downstream effector proteins involved in cytoskeletal regulation. RhoA is implicated in the formation of actin stress fibers, focal adhesion and actinomyosin assembly. RhoA binds and activates Rho kinase (ROCK), which has several downstream cytoskeletal targets. ROCK increases myosin light chain (MYL) phosphorylation by directly phosphorylating MYL and by inhibiting the myosin light chain phosphatase (MLCP), leading to actinomyosin assembly. ROCK also phosphorylates LIM-kinase (LIMK), which subsequently phosphorylates the actin depolymerizing protein, cofilin, inhibiting its function. Cofilin inhibition leads to stabilization of actin. In addition, ROCK increases the activity of the Na+/H+ exchange protein NHE1 and the PI4P5K, potentiating stress fiber formation and focal adhesion assembly. On the other hand, integrin ligation stimulate the c-Src-dependent activation of GRLF1, which suppresses RhoA activity. The direct binding between integrins and FAK leads to the activation of the FAK-CAS-CRK-DOCK1-Rac pathway, which also antagonizes RhoA activity. Activated Rac and Cdc42 activate PAK which disassembles stress fibers and focal adhesion, through inactivation of MLCK and stabilizes actin filaments, through activation of LIMK. IQGAP is a scaffolding protein downstream of Rac and Cdc42, which promotes formation of adherens junctions. While RhoA causes the formation of stress fibers, stimulation of Rac, through the activation of WAVE and the Arp2/3-actin complex, induces the formation of lamellipodia and activation of Cdc42 leads to the formation of filopodia, through the binding to NWASP.