title: PTP-PEST couples membrane protrusion and tail retraction via VAV2 and p190RhoGAP.
abstract: Cell motility is regulated by a balance between forward protrusion and tail retraction. These phenomena are controlled by a spatial asymmetry in signals at the front and the back of the cell. We show here that the protein-tyrosine phosphatase, PTP-PEST, is required for the coupling of protrusion and retraction during cell migration. PTP-PEST null fibroblasts, which are blocked in migration, exhibit exaggerated protrusions at the leading edge and long, unretracted tails in the rear. This altered morphology is accompanied by changes in the activity of Rho GTPases, Rac1 and RhoA, which mediate protrusion and retraction, respectively. PTP-PEST null cells exhibit enhanced Rac1 activity and decreased RhoA activity. We further show that PTP-PEST directly targets the upstream regulators of Rac1 and RhoA, VAV2 and p190RhoGAP. Moreover, we demonstrate that the activities of VAV2 and p190RhoGAP are regulated by PTP-PEST. Finally, we present evidence indicating the VAV2 can be regulated by integrin-mediated adhesion. These data suggest that PTP-PEST couples protrusion and retraction by acting on VAV2 and p190RhoGAP to reciprocally modulate the activity of Rac1 and RhoA.
authors.affiliation: Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1048, USA. sasastry@utmb.edu
authors.forename: Sarita K
authors.initials: SK
authors.lastname: Sastry
authors.forename: Zenon
authors.initials: Z
authors.lastname: Rajfur
authors.forename: Betty P
authors.initials: BP
authors.lastname: Liu
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Cote
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: Keith
authors.initials: K
authors.lastname: Burridge
mesh_terms: D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D022081:Cell Surface Extensions / Q000201:enzymology* / Q000648:ultrastructure; D006224:Cricetinae; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D005455:Fluorescent Antibody Technique; D020690:GTPase-Activating Proteins; D047468:Immunoprecipitation; D016023:Integrins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D013623:Tail / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C513041:Arhgap35 protein, mouse; C513042:Arhgap5 protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D016023:Integrins; D051567:Proto-Oncogene Proteins c-vav; D012097:Repressor Proteins; C490565:Vav2 protein, mouse; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D017027:Protein Tyrosine Phosphatases; C516739:Ptpn12 protein, mouse; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein