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Molecular and Cellular Biology, August 2002, p. 5897-5911, Vol. 22, No. 16
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.16.5897-5911.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Site-Directed Perturbation of Protein Kinase C- Integrin Interaction Blocks Carcinoma Cell Chemotaxis

Maddy Parsons,1 Melanie D. Keppler,1 Adam Kline,2 Anthea Messent,2 Martin J. Humphries,2 Ruth Gilchrist,1 Ian R. Hart,1 Corinne Quittau-Prevostel,3,{dagger} William E. Hughes,3,{ddagger} Peter J. Parker,3 and Tony Ng1*

Richard Dimbleby/Cancer Research UK Department of Cancer Research, GKT School of Medicine, St. Thomas' Hospital, London SE1 7EH,1 Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, University of Manchester, Manchester M13 9PT,2 Protein Phosphorylation Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom3

Received 27 February 2002/ Returned for modification 4 April 2002/ Accepted 22 May 2002

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 C{alpha} (PKC{alpha}) 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 PKC{alpha} V3 hinge domain. This motif is also required for a direct association between PKC{alpha} and ß1 integrin. Efficient binding of ß1 integrin to PKC{alpha} 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 ß1 integrin was shown to block both PKC{alpha}-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 PKC{alpha} and ß1 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.

* Corresponding author. Mailing address: Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. Phone: 44(0) 207-269-3054. E-mail: T.Ng{at}cancer.org.uk.

{dagger} Present address: INSERM U469, 34090 Montpellier, France.

{ddagger} Present address: The Garvan Institute of Medical Research, Sydney, New South Wales 2101, Australia.

Molecular and Cellular Biology, August 2002, p. 5897-5911, Vol. 22, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.16.5897-5911.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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