Cytoskeletal Signaling
Pathway Description:
Signaling to the cytoskeleton through G protein coupled receptors (GPCRs), integrins and receptor tyrosine kinases (RTKs) can lead to diverse effects on the cell’s activity, including changes in cell shape, migration, proliferation and survival. Integrins, in conjunction with other components of focal adhesion (FA) complexes, serve as the link between the extracellular matrix and the cytoskeleton. Integrin activation leads to activation of focal adhesion kinase (FAK) and Src kinase, resulting in the phosphorylation of other FA components such as paxillin and the Crk-associated substrate p130 CAS, as well as the recruitment of signaling adaptor proteins. This is accompanied by actin assembly, in addition to changes in FA dynamics and FA turnover.
In a similar fashion, RTKs utilize intrinsic tyrosine kinase activity to phosphorylate sites on their intracellular loops and/or on associated signaling components. This leads to the recruitment of adaptor proteins and signaling kinases that modulate downstream mediators of phosphoinositide signaling, small GTPase activation, and MAP kinase cascades. GPCR utilize heterotrimeric G protein-initiated second messengers to couple to similar signaling mechanisms impacting on actin dynamic behavior.
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), as well as downstream protein kinase effectors, including Rho-kinase/ROCK and p21 activated kinase (PAK). These cascades converge on proteins that directly regulate the behavior of the actin cytoskeleton, including actin interacting regulatory proteins such as cofilin, Arp2/3, Ena/VASP, formins, 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 cell.
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.
Selected Reviews:
- Bamburg JR, Wiggan OP (2002) ADF/cofilin and actin dynamics in disease. Trends Cell Biol. 12(12), 598–605.
- Bokoch GM (2003) Biology of the p21-activated kinases. Annu. Rev. Biochem. 72, 743–81.
- Danuser G (2005) Coupling the dynamics of two actin networks--new views on the mechanics of cell protrusion. Biochem. Soc. Trans. 33(Pt 6), 1250–3.
- Pollard TD, Borisy GG (2003) Cellular motility driven by assembly and disassembly of actin filaments. Cell 112(4), 453–65.
- Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, Parsons JT, Horwitz AR (2003) Cell migration: integrating signals from front to back. Science 302(5651), 1704–9.
CST would like to thank Prof. Gary M. Bokoch, Departments of Immunology and Cell Biology, The Scripps Research Institute, La Jolla, California, and Prof. James R. Bamburg, Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, for contributing to this diagram.
created January 2004 • revised January 2007
