Alpha v beta3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration.
Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of beta3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of beta3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to beta1 integrin. These data demonstrate a novel mechanism by which alphavbeta3 integrin acts to locally suppress beta1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.
Worth
Daniel C
DC
Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, England, UK.
Hodivala-Dilke
Kairbaan
K
Robinson
Stephen D
SD
King
Samantha J
SJ
Morton
Penny E
PE
Gertler
Frank B
FB
Humphries
Martin J
MJ
Parsons
Maddy
M
D000199:Actins / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016608:Talin / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D039302:Integrin alphaVbeta3; D008565:Membrane Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; C521189:RIAM protein, mouse; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D016608:Talin; D000098662:Vasodilator-Stimulated Phosphoprotein; D017868:Cyclic AMP-Dependent Protein Kinases; D020827:rap1 GTP-Binding Proteins
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