Site-directed perturbation of protein kinase C- integrin interaction blocks carcinoma cell chemotaxis.
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 beta 1 integrin. Efficient binding of beta 1 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 beta 1 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 beta 1 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.
Mesh Terms:
Amino Acid Motifs, Antennapedia Homeodomain Protein, Antigens, CD29, Apoptosis, Binding Sites, Breast Neoplasms, Chemotaxis, Female, Homeodomain Proteins, Humans, In Situ Nick-End Labeling, Isoenzymes, Microscopy, Fluorescence, Nuclear Proteins, Peptides, Protein Binding, Protein Kinase C, Protein Kinase C-alpha, Recombinant Fusion Proteins, Transcription Factors, Transduction, Genetic, Tumor Cells, Cultured
Amino Acid Motifs, Antennapedia Homeodomain Protein, Antigens, CD29, Apoptosis, Binding Sites, Breast Neoplasms, Chemotaxis, Female, Homeodomain Proteins, Humans, In Situ Nick-End Labeling, Isoenzymes, Microscopy, Fluorescence, Nuclear Proteins, Peptides, Protein Binding, Protein Kinase C, Protein Kinase C-alpha, Recombinant Fusion Proteins, Transcription Factors, Transduction, Genetic, Tumor Cells, Cultured
Mol. Cell. Biol.
Date: Aug. 01, 2002
PubMed ID: 12138200
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