PTP{alpha} regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration

doi:10.1083/jcb.200206049

Published 6 January 2003. doi:10.1083/jcb.200206049

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© The Rockefeller University Press, 0021-9525/2003/1/137 $5.00
The Journal of Cell Biology, Volume 160, Number 1, 137-146

Article

PTP ${alpha}$ regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration

Li Zeng¹, Xiaoning Si¹^,2^,3, Wei-Ping Yu¹, Hoa Thi Le¹^,2^,3, Kwok Peng Ng¹, Raymond M.H. Teng¹, Kenneth Ryan²^,3, Dennis Z.-M. Wang¹, Sathivel Ponniah¹ and Catherine J. Pallen¹^,2^,3

¹ Cell Regulation Laboratory, Institute of Molecular and Cell Biology, Singapore 117609, Singapore
² Department of Pediatrics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada
³ British Columbia Research Institute for Children's and Women's Health, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada

Address correspondence to Catherine J. Pallen, Dept. of Pediatrics, University of British Columbia, B.C. Research Institute for Children's and Women's Health, Rm. 3102, 950 West 28th Ave., Vancouver, British Columbia V5Z 4H4, Canada. Tel.: (604) 875-2439. Fax: (604) 875-2417. E-mail: cpallen{at}interchange.ubc.ca

We investigated the molecular and cellular actions of receptorprotein tyrosine phosphatase (PTP) ${alpha}$ in integrin signaling usingimmortalized fibroblasts derived from wild-type and PTP ${alpha}$ -deficientmouse embryos. Defects in PTP ${alpha}$ ^-/- migration in a wound healingassay were associated with altered cell shape and focal adhesionkinase (FAK) phosphorylation. The reduced haptotaxis to fibronectin(FN) of PTP ${alpha}$ ^-/- cells was increased by expression of active (butnot inactive) PTP ${alpha}$ . Integrin-mediated formation of src–FAKand fyn–FAK complexes was reduced or abolished in PTP ${alpha}$ ^-/-cells on FN, concomitant with markedly reduced phosphorylationof FAK at Tyr397. Reintroduction of active (but not inactive)PTP ${alpha}$ restored FAK Tyr-397 phosphorylation. FN-induced cytoskeletalrearrangement was retarded in PTP ${alpha}$ ^-/- cells, with delayed filamentousactin stress fiber assembly and focal adhesion formation. Thismimicked the effects of treating wild-type fibroblasts withthe src family protein tyrosine kinase (Src-PTK) inhibitor PP2.These results, together with the reduced src/fyn tyrosine kinaseactivity in PTP ${alpha}$ ^-/- fibroblasts (Ponniah et al., 1999; Su et al., 1999),suggest that PTP ${alpha}$ functions in integrin signalingand cell migration as an Src-PTK activator. Our paper establishesthat PTP ${alpha}$ is required for early integrin-proximal events, actingupstream of FAK to affect the timely and efficient phosphorylationof FAK Tyr-397.

Key Words: Src-PTKs; protein tyrosine phosphatase; focal adhesion; actin

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