title: Spatial restriction of alpha4 integrin phosphorylation regulates lamellipodial stability and alpha4beta1-dependent cell migration.
abstract: Integrins coordinate spatial signaling events essential for cell polarity and directed migration. Such signals from alpha4 integrins regulate cell migration in development and in leukocyte trafficking. Here, we report that efficient alpha4-mediated migration requires spatial control of alpha4 phosphorylation by protein kinase A, and hence localized inhibition of binding of the signaling adaptor, paxillin, to the integrin. In migrating cells, phosphorylated alpha4 accumulated along the leading edge. Blocking alpha4 phosphorylation by mutagenesis or by inhibition of protein kinase A drastically reduced alpha4-dependent migration and lamellipodial stability. alpha4 phosphorylation blocks paxillin binding in vitro; we now find that paxillin and phospho-alpha4 were in distinct clusters at the leading edge of migrating cells, whereas unphosphorylated alpha4 and paxillin colocalized along the lateral edges of those cells. Furthermore, enforced paxillin association with alpha4 inhibits migration and reduced lamellipodial stability. These results show that topographically specific integrin phosphorylation can control cell migration and polarization by spatial segregation of adaptor protein binding.
authors.affiliation: Department of Cell Biology, Division of Vascular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, VB-2 La Jolla, CA 92037, USA.
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Goldfinger
authors.forename: Jaewon
authors.initials: J
authors.lastname: Han
authors.forename: William B
authors.initials: WB
authors.lastname: Kiosses
authors.forename: Alan K
authors.initials: AK
authors.lastname: Howe
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
mesh_terms: D000818:Animals; D016466:CHO Cells; D002465:Cell Movement / Q000502:physiology*; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000378:metabolism; D039441:Integrin alpha4 / Q000378:metabolism*; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011554:Pseudopodia / Q000378:metabolism*; D051381:Rats
chemical_list: D003598:Cytoskeletal Proteins; D039041:Integrin alpha4beta1; D051419:Paxillin; D010750:Phosphoproteins; C496063:Pxn protein, rat; D039441:Integrin alpha4