TY - JOUR
T1 - αvβ3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration
AU - Worth, Daniel C.
AU - Hodivala-Dilke, Kairbaan
AU - Robinson, Stephen D.
AU - King, Samantha J.
AU - Morton, Penny E.
AU - Gertler, Frank B.
AU - Humphries, Martin J.
AU - Parsons, Maddy
PY - 2010/4/19
Y1 - 2010/4/19
N2 - 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 beta 3 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 beta 3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta 3-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 beta 1 integrin. These data demonstrate a novel mechanism by which alpha nu beta 3 integrin acts to locally suppress beta 1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.
AB - 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 beta 3 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 beta 3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in beta 3-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 beta 1 integrin. These data demonstrate a novel mechanism by which alpha nu beta 3 integrin acts to locally suppress beta 1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.
U2 - 10.1083/jcb.200912014
DO - 10.1083/jcb.200912014
M3 - Article
VL - 189
SP - 369
EP - 383
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 2
ER -