The C terminus of c-Src inhibits breast tumor cell growth by a kinase-independent mechanism. 2004

Rumey C Ishizawar, and David A Tice, and Themistoclis Karaoli, and Sarah J Parsons
Department of Microbiology and Cancer Center, University of Virginia Health Services, Charlottesville, Virginia 22908, USA.

Overexpression or increased activity of cellular Src (c-Src) is frequently detected in human breast cancer, implicating involvement of c-Src in the etiology of breast carcinomas. Curiously, overexpression of c-Src in tissue culture cells results in a weakly or non-transforming phenotype, indicating that it alone is not sufficient for oncogenesis. However, the protein has been demonstrated to potentiate mitogenic signals from transmembrane receptors. This report investigates the requirement for c-Src in breast cancer as a transducer and integrator of anchorage-dependent and -independent growth signals by utilizing the Src family pharmacological inhibitors, PP1 and PP2, or stable overexpression of the catalytically inactive c-Src mutant (K- c-Src). Both methods of inhibiting endogenous c-Src diminished formation of soft agar colonies and tumors in nude mice. The majority of the dominant-negative activity of K- c-Src was mapped to the Src homology 2 (SH2) domain and C-terminal half of the molecule, but not to the Unique domain, Src homology 3 (SH3) domain, or the N-terminal half of K- c-Src. Further analysis of the C terminus revealed that its ability to inhibit growth localized to the N-terminal lobe (N-lobe) of the catalytic region. These results underscore the requirement for c-Src to maintain the oncogenic phenotype of breast cancer cells and suggest that c-Src may be manipulated to inhibit cell growth by the direct disruption of its catalytic activity or the introduction of either the SH2 domain or the N-lobe of K- c-Src.

UI MeSH Term Description Entries
D010770 Phosphotransferases A rather large group of enzymes comprising not only those transferring phosphate but also diphosphate, nucleotidyl residues, and others. These have also been subdivided according to the acceptor group. (From Enzyme Nomenclature, 1992) EC 2.7. Kinases,Phosphotransferase,Phosphotransferases, ATP,Transphosphorylase,Transphosphorylases,Kinase,ATP Phosphotransferases
D011505 Protein-Tyrosine Kinases Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors. Tyrosine Protein Kinase,Tyrosine-Specific Protein Kinase,Protein-Tyrosine Kinase,Tyrosine Kinase,Tyrosine Protein Kinases,Tyrosine-Specific Protein Kinases,Tyrosylprotein Kinase,Kinase, Protein-Tyrosine,Kinase, Tyrosine,Kinase, Tyrosine Protein,Kinase, Tyrosine-Specific Protein,Kinase, Tyrosylprotein,Kinases, Protein-Tyrosine,Kinases, Tyrosine Protein,Kinases, Tyrosine-Specific Protein,Protein Kinase, Tyrosine-Specific,Protein Kinases, Tyrosine,Protein Kinases, Tyrosine-Specific,Protein Tyrosine Kinase,Protein Tyrosine Kinases,Tyrosine Specific Protein Kinase,Tyrosine Specific Protein Kinases
D011518 Proto-Oncogene Proteins Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity. Cellular Proto-Oncogene Proteins,c-onc Proteins,Proto Oncogene Proteins, Cellular,Proto-Oncogene Products, Cellular,Cellular Proto Oncogene Proteins,Cellular Proto-Oncogene Products,Proto Oncogene Products, Cellular,Proto Oncogene Proteins,Proto-Oncogene Proteins, Cellular,c onc Proteins
D001943 Breast Neoplasms Tumors or cancer of the human BREAST. Breast Cancer,Breast Tumors,Cancer of Breast,Breast Carcinoma,Cancer of the Breast,Human Mammary Carcinoma,Malignant Neoplasm of Breast,Malignant Tumor of Breast,Mammary Cancer,Mammary Carcinoma, Human,Mammary Neoplasm, Human,Mammary Neoplasms, Human,Neoplasms, Breast,Tumors, Breast,Breast Carcinomas,Breast Malignant Neoplasm,Breast Malignant Neoplasms,Breast Malignant Tumor,Breast Malignant Tumors,Breast Neoplasm,Breast Tumor,Cancer, Breast,Cancer, Mammary,Cancers, Mammary,Carcinoma, Breast,Carcinoma, Human Mammary,Carcinomas, Breast,Carcinomas, Human Mammary,Human Mammary Carcinomas,Human Mammary Neoplasm,Human Mammary Neoplasms,Mammary Cancers,Mammary Carcinomas, Human,Neoplasm, Breast,Neoplasm, Human Mammary,Neoplasms, Human Mammary,Tumor, Breast
D002455 Cell Division The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION. M Phase,Cell Division Phase,Cell Divisions,Division Phase, Cell,Division, Cell,Divisions, Cell,M Phases,Phase, Cell Division,Phase, M,Phases, M
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000081247 CSK Tyrosine-Protein Kinase Protein tyrosine kinases that phosphorylate tyrosine residues located in the C-terminal tails of SRC-FAMILY KINASES. C-Terminal Src Kinase,Carboxy-Terminal Src Kinase,Protein Tyrosine Kinase p50(csk),Protein-Tyrosine Kinase C-Terminal Src Kinase,Protein-Tyrosine Kinase c-src,Tyrosine Protein Kinase p50csk,Tyrosine-Protein Kinase CSK,c-src Kinase,c-src Tyrosine Kinase,CSK-src,p50(csk),C Terminal Src Kinase,CSK Tyrosine Protein Kinase,CSK src,CSK, Tyrosine-Protein Kinase,Carboxy Terminal Src Kinase,Kinase CSK, Tyrosine-Protein,Kinase c-src, Protein-Tyrosine,Kinase, C-Terminal Src,Kinase, CSK Tyrosine-Protein,Kinase, Carboxy-Terminal Src,Kinase, c-src,Kinase, c-src Tyrosine,Protein Tyrosine Kinase C Terminal Src Kinase,Protein Tyrosine Kinase c src,Src Kinase, C-Terminal,Src Kinase, Carboxy-Terminal,Tyrosine Kinase, c-src,Tyrosine Protein Kinase CSK,Tyrosine-Protein Kinase, CSK,c src Kinase,c src Tyrosine Kinase,c-src, Protein-Tyrosine Kinase
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D015972 Gene Expression Regulation, Neoplastic Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in neoplastic tissue. Neoplastic Gene Expression Regulation,Regulation of Gene Expression, Neoplastic,Regulation, Gene Expression, Neoplastic

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