Site-directed perturbation of protein kinase C-integrin interaction blocks carcinoma cell chemotaxis

被引:89
作者
Parsons, M
Keppler, MD
Kline, A
Messent, A
Humphries, MJ
Gilchrist, R
Hart, IR
Quittau-Prevostel, C
Hughes, WE
Parker, PJ
Ng, T
机构
[1] Canc Res UK London Res Inst, Prot Phosphorylat Lab, London WC2A 3PX, England
[2] Univ Manchester, Sch Biol Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England
[3] St Thomas Hosp, GKT Sch Med, Richard Dimbleby Canc Res UK Dept Canc Res, London SE1 7EH, England
关键词
D O I
10.1128/MCB.22.16.5897-5911.2002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Polarized cell movement is an essential requisite for cancer metastasis; thus, interference with the tumor cell motility machinery would significantly modify its metastatic behavior. Protein kinase Calpha (PKCalpha) has been implicated in the promotion of a migratory cell phenotype. We report that the phorbol ester-induced cell polarization and directional motility in breast carcinoma cells is determined by a 12-amino-acid motif (amino acids 313 to 325) within the PKCalpha V3 hinge domain. This motif is also required for a direct association between PKCalpha and beta1 integrin. Efficient binding of beta1 integrin to PKCalpha requires the presence of both NPXY motifs (Cyto-2 and Cyto-3) in the integrin distal cytoplasmic domains. A cell-permeant inhibitor based on the PKC-binding sequence of beta1 integrin was shown to block both PKCalpha-driven and epidermal growth factor (EGF)-induced chemotaxis. When introduced as a minigene by retroviral transduction into human breast carcinoma cells, this inhibitor caused a striking reduction in chemotaxis towards an EGF gradient. Taken together, these findings identify a direct link between PKCalpha and beta1 integrin that is critical for directed tumor cell migration. Importantly, our findings outline a new concept as to how carcinoma cell chemotaxis is enhanced and provide a conceptual basis for interfering with tumor cell dissemination.
引用
收藏
页码:5897 / 5911
页数:15
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