The p16(INK4a) tumour suppressor protein inhibits alpha(v)beta(3) integrin-mediated cell spreading on vitronectin by blocking PKC-dependent localization of alpha(v)beta(3) to focal contacts
R. Fahraeus et Dp. Lane, The p16(INK4a) tumour suppressor protein inhibits alpha(v)beta(3) integrin-mediated cell spreading on vitronectin by blocking PKC-dependent localization of alpha(v)beta(3) to focal contacts, EMBO J, 18(8), 1999, pp. 2106-2118
Expression of full-length p16(INK4a) blocks alpha(v)beta(3) integrin-depend
ent cell spreading on vitronectin but not collagen IV. Similarly, G(1)-asso
ciated cell cycle kinases (CDK) inhibitory (CKI) synthetic peptides derived
from p16(INK4a), p18(INK4c) and p21(Cip1/Waf1), which can be delivered dir
ectly into cells from the tissue culture medium, do not affect non-alpha(v)
beta(3)-dependent spreading on collagen IV, laminin and fibronectin at conc
entrations that inhibit cell cycle progression in late G(1). The alpha(v)be
ta(3) heterodimer remains intact after CKI peptide treatment but is immedia
tely dissociated from the focal adhesion contacts, Treatment with phorbol 1
2-myristate 13-acetate allows alpha(v)beta(3) to locate to the focal adhesi
on contacts and the cells to spread on vitronectin in the presence of CKI p
eptides, The cdk6 protein is found to suppress p16(INK4a)-mediated inhibiti
on of spreading and is also shown to localize to the ruffling edge of sprea
ding cells, indicating a function for cdk6 in controlling matrix-dependent
cell spreading, These results demonstrate a novel G(1) CDK-associated integ
rin regulatory pathway that acts upstream of alpha(v)beta(3)-dependent acti
vation of PKC as well as a novel function for the p16(INK4a) tumour suppres
sor protein in regulating matrix-dependent cell migration.