alpha v beta3 and alpha5beta1 integrin recycling pathways dictate downstream Rho kinase signaling to regulate persistent cell migration.
Accumulating evidence suggests that integrin recycling regulates cell migration. However, the lack of reagents to selectively target the trafficking of individual heterodimers, as opposed to endocytic transport as a whole, has made it difficult to define the contribution made by particular recycling pathways to directional cell movement. We show that autophosphorylation of protein kinase D1 (PKD1) at Ser(916) is necessary for its association with alphavbeta3 integrin. Expression of PKD1(916A) or the use of mutants of beta3 that do not bind to PKD1 selectively inhibits short-loop, Rab4-dependent recycling of alphavbeta3, and this suppresses the persistence of fibroblast migration. However, we report that short-loop recycling does not directly contribute to fibroblast migration by moving alphavbeta3 to the cell front, but by antagonizing alpha5beta1 recycling, which, in turn, influences the cell's decision to migrate with persistence or to move randomly.
White
Dominic P
DP
Integrin Cell Biology Laboratory, Beatson Institute for Cancer Research, Bearsden, Glasgow, Scotland, UK.
Caswell
Patrick T
PT
Norman
Jim C
JC
D000818:Animals; D019556:COS Cells; D002465:Cell Movement / Q000235:genetics; D002522:Chlorocebus aethiops; D004705:Endocytosis / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D020695:rab4 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases
D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D047908:Intracellular Signaling Peptides and Proteins; C089212:protein kinase D; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D020695:rab4 GTP-Binding Proteins