Alpha(v)beta3 integrin expression up-regulates cdc2, which modulates cell migration.
The alphavbeta3 integrin has been shown to promote cell migration through activation of intracellular signaling pathways. We describe here a novel pathway that modulates cell migration and that is activated by alphavbeta3 and, as downstream effector, by cdc2 (cdk1). We report that alphavbeta3 expression in LNCaP (beta3-LNCaP) prostate cancer cells causes increased cdc2 mRNA levels as evaluated by gene expression analysis, and increased cdc2 protein and kinase activity levels. We provide three lines of evidence that increased levels of cdc2 contribute to a motile phenotype on integrin ligands in different cell types. First, increased levels of cdc2 correlate with more motile phenotypes of cancer cells. Second, ectopic expression of cdc2 increases cell migration, whereas expression of dominant-negative cdc2 inhibits migration. Third, cdc2 inhibitors reduce cell migration without affecting cell adhesion. We also show that cdc2 increases cell migration via specific association with cyclin B2, and we unravel a novel pathway of cell motility that involves, downstream of cdc2, caldesmon. cdc2 and caldesmon are shown here to localize in membrane ruffles in motile cells. These results show that cdc2 is a downstream effector of the alphavbeta3 integrin, and that it promotes cell migration.
Manes
Thomas
T
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
Zheng
Duo-Qi
DQ
Tognin
Simona
S
Woodard
Amy S
AS
Marchisio
Pier Carlo
PC
Languino
Lucia R
LR
D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002465:Cell Movement; D019926:Cyclin B / Q000378:metabolism; D056765:Cyclin B2; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
C503758:CCNB2 protein, human; D002148:Calmodulin-Binding Proteins; D019926:Cyclin B; D056765:Cyclin B2; D039302:Integrin alphaVbeta3; D012333:RNA, Messenger; D016203:CDC2 Protein Kinase