Characterization of a novel negative regulator (DOC-2/DAB2) of c-Src in normal prostatic epithelium and cancer.
DOC-2/DAB2 is a potent tumor suppressor in many cancer types including prostate cancer. In prostate cancer, expression of DOC-2/DAB2 can inhibit its growth. Our recent studies demonstrate that DOC-2/DAB2 can suppress both protein kinase C and peptide growth factor-elicited signal pathways via the Ras-mitogen-activated protein kinase pathway. In this study, we further showed that the proline-rich domain of DOC-2/DAB2 could also interact with proteins containing the Src homology 3 domain, such as Src and Fgr. The binding of c-Src to DOC-2/DAB2 was enhanced in cells treated with growth factor, and this interaction resulted in c-Src inactivation. The c-Src inactivation was evidenced by the decreased tyrosine 416 phosphorylation of c-Src and reduced downstream effector activation. It appears that DOC-2/DAB2 can bind to Src homology 3 domain of c-Src and maintain it in an inactive conformation. Thus, this study provides a new mechanism for modulating c-Src in prostatic epithelium and cancer.
Zhou
Jian
J
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9110, USA.
Scholes
Jessica
J
Hsieh
Jer-Tsong
JT
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D019556:COS Cells; D000081247:CSK Tyrosine-Protein Kinase; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016147:Genes, Tumor Suppressor; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D014176:Protein Biosynthesis; D011487:Protein Conformation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D004791:Enzyme Inhibitors; D010455:Peptides; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D014443:Tyrosine; D005982:Glutathione Transferase; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases