Regulation of Actin Dynamics Signaling Pathway
Signaling to the cytoskeleton through G protein-coupled receptors (GPCRs), integrins, receptor tyrosine kinases (RTKs), and numerous other specialized receptors, such as the semaphorin 1a receptor PlexinA, can lead to diverse effects on cell activity, including changes in cell shape, migration, proliferation, and survival. Integrins, in conjuction with other components of focal adhesion complexes, serve as the link between the extracellular matrix and cytoskeleton in many cell types. Integrin activation leads to activation of focal adhesion kinase (FAK) and Src kinase, resulting in phosphorylation of other FA components such as paxillin and the Crk-associated substrate p130 Cas, as well as the recruitment of signaling adapter proteins.
Intracellular regulation of the cell’s response to external cues occurs through a large number of signaling cascades that include the Rho family of small GTPases (Rho, Rac, and Cdc42) and their activators, guanine nucleotide exchange factors (GEFs), their downstream protein kinase effectors, including Rho-kinase/ROCK and p21 activated kinase (PAK), as well as through direct binding of the GTPases to several actin regulatory proteins, such as cortactin, mDia, WAVE, and WASP. These cascades converge on proteins that directly regulate the behavior and organization of the actin cytoskeleton, including actin interacting regulatory proteins such as cofilin, Arp2/3 complex, Ena/VASP, forminins, profilin, and gelsolin. Signaling through different pathways can lead to the formation of distinct actin-dependent structures whose coordinated assembly/disassembly is important for directed cell migration and other cellular behaviors. Migration is also regulated by signaling to myosin, which participates in leading edge actin dynamics and enables retraction of the rear of the cells. Tropomyosins stabilize F-actin by preventing binding of severing and dynamizing factors. Some tropomyosins may also enhance filament dynamics. Dynamic actin is required for most cellular actin-dependent processes; inhibiting actin assembly and preventing actin disassembly are equally inhibitory to most behaviors.
Aberrant control of cytoskeletal signaling, which can result in a disconnection between extracellular stimuli and cellular responses, is often seen in immune pathologies, developmental defects, and cancer.
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We would like to thank Prof. James Bamburg, Colorado State University, Fort Collins, CO for updates to the Regulation of Actin Dynamics and the Regulation of Microtubule Dynamics pathways.
created September 2008
revised September 2012