Migration of cells is involved in essential functions such as development, invasiveness of cancer cells, leukocyte movement toward chemotactic signals, and fibroblast response to injury. Cells can migrate in a specific direction in response to extracellular signals through pathways that trigger changes in the cytoskeleton, particularly actin filaments, increasing lamellipodia and filopodia formation and decreasing focal adhesions. Factors like PDGF activate PI3 kinase and multiple pathways downstream to stimulate cell migration. One pathway regulating migration through the p85 regulatory subunit of PI3 kinase does not require PI3-kinase activity. In this pathway, p85 of PI3-kinase activates cdc42, which activates N-Wasp (Wiskott-Aldrich Syndrome Protein) to regulate ARP-2/3. ARP-2/3 is a complex of proteins localized at the leading edge of moving cells that nucleates the formation of new actin fibers and interacts with Wasp to stimulate migration. The cdc42 pathway also regulates p21-activate kinase 1 (PAK1). Another pathway by which PI3 kinase regulates migration is through the small GTPase Rac. PAK1 is a downstream target of Rac as well as cdc42. Downstream of Rac and PAK1, Myosin light chain kinase (MLCK) phosphorylates myosin light chain to increase cell migration. The regulation of the localization and activity of signaling factors creates coordinated pathways linking extracellular signals and cellular migration.

Contributor: Glenn Croston, PhD

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