Dissection of HEF1-dependent functions in motility and transcriptional regulation.
Cas-family proteins have been implicated as signaling intermediaries in diverse processes including cellular attachment, motility, growth factor response, apoptosis and oncogenic transformation. The three defined Cas-family members (p130Cas, HEF1/Cas-L and Efs/Sin) are subject to multiple forms of regulation (including cell-cycle- and cell-attachment-mediated post-translational modification and cleavage) that complicate elucidation of the function of specific Cas proteins in defined biological processes. To explore the biological role of HEF1 further, we have developed a series of cell lines in which HEF1 production is regulated by an inducible promoter. In this system, HEF1 production rapidly induces changes in cellular morphology and motility, enhancing cell speed and haptotaxis towards fibronectin in a process partially dependent on intact ERK and p38 MAPK signaling pathways. Finally, cDNA expression array analysis and subsequent studies indicate that HEF1 production increases levels of mRNA transcripts encoding proteins that are associated with motility, cell transformation and invasiveness, including several metalloproteinases, MLCK, p160ROCK and ErbB2. Upregulation of such proteins suggests mechanisms through which misregulation of HEF1 may be involved in cancer progression.
Fashena
Sarah J
SJ
Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111, USA.
Einarson
Margret B
MB
O'Neill
Geraldine M
GM
Patriotis
Christos
C
Golemis
Erica A
EA
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000906:Antibodies / Q000276:immunology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D048429:Cell Size; D002999:Clone Cells; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D018613:Microscopy, Confocal; D018715:Microscopy, Video; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000276:immunology / Q000502:physiology*; D011401:Promoter Regions, Genetic; D013752:Tetracycline / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013752:Tetracycline