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The p16 INK4a tumour suppressor protein inhibits α v β 3 integrin‐mediated cell spreading on vitronectin by blocking PKC‐dependent localization of α v β 3 to focal contacts
Author(s) -
Fåhraeus Robin,
Lane David P.
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.8.2106
Subject(s) - vitronectin , biology , integrin , suppressor , alpha (finance) , microbiology and biotechnology , alpha v beta 3 , protein kinase c , blocking (statistics) , cancer research , biophysics , cell , signal transduction , biochemistry , gene , medicine , construct validity , statistics , nursing , mathematics , patient satisfaction
Expression of full‐length p16 INK4a blocks α v β 3 integrin‐dependent cell spreading on vitronectin but not collagen IV. Similarly, G 1 ‐associated cell cycle kinases (CDK) inhibitory (CKI) synthetic peptides derived from p16 INK4a , p18 INK4c and p21 Cip1/Waf1 , which can be delivered directly into cells from the tissue culture medium, do not affect non‐α v β 3 ‐dependent spreading on collagen IV, laminin and fibronectin at concentrations that inhibit cell cycle progression in late G 1 . The α v β 3 heterodimer remains intact after CKI peptide treatment but is immediately dissociated from the focal adhesion contacts. Treatment with phorbol 12‐myristate 13‐acetate (PMA) allows α v β 3 to locate to the focal adhesion contacts and the cells to spread on vitronectin in the presence of CKI peptides. The cdk6 protein is found to suppress p16 INK4a ‐mediated inhibition of spreading and is also shown to localize to the ruffling edge of spreading cells, indicating a function for cdk6 in controlling matrix‐dependent cell spreading. These results demonstrate a novel G 1 CDK‐associated integrin regulatory pathway that acts upstream of α v β 3 ‐dependent activation of PKC as well as a novel function for the p16 INK4a tumour suppressor protein in regulating matrix‐dependent cell migration.