Regulation of Actin Dynamics

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Search this pathway for protein information from PhosphoSitePlus^®, our expert-curated knowledge base of protein phosphorylation and other post-translational modifications.

Pathway Description:

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 the cells 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 p130CAS, as well as the recruitment of signaling adapter proteins. Cofilin, a recently discovered substrate of Src on Tyr68, is targeted for proteasome degradation when phosphorylated on this site. This localized change in cofilin activity along with other signaling pathways, results in actin assembly at the focal adhesion.

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. Multiple isoforms of tropomyosin are expressed in cells from higher animals and some of these stabilize F-actin by preventing binding of severing and dynamizing factors. However, 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. Hyperactivation of cofilin through its regulatory pathways in response to cell stress can lead to cofilin-saturated filament bundles that assemble into rod-like structures. In neurons, rods may be responsible for inhibition of neurite transport and synaptic loss in many cognitive disorders.

Selected Reviews:

• Bernstein BW, Bamburg JR (2010) ADF/cofilin: a functional node in cell biology. Trends Cell Biol. 20(4), 187–95.
• Hung RJ, Yazdani U, Yoon J, Wu H, Yang T, Gupta N, Huang Z, van Berkel WJ, Terman JR (2010) Mical links semaphorins to F-actin disassembly. Nature 463(7282), 823–7.
• Lee SH, Dominguez R (2010) Regulation of actin cytoskeleton dynamics in cells. Mol. Cells 29(4), 311–25.
• Van Troys M, Huyck L, Leyman S, Dhaese S, Vandekerkhove J, Ampe C (2008) Ins and outs of ADF/cofilin activity and regulation. Eur. J. Cell Biol. 87(8-9), 649–67.

We would like to thank Prof. James Bamburg, Colorado State University, for recent updates to the Regulation of Actin Dynamics and the Regulation of Microtubule Dynamics pathways.