Role of Src Signal Transduction Pathways in Scatter Factor-mediated Cellular Protection

• Published in: The Journal of biological chemistry Vol. 284; no. 12; pp. 7561 - 7577
• Main Authors: Fan, Saijun, Meng, Qinghui, Laterra, John J., Rosen, Eliot M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.03.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Cell Line, Tumor; Dogs; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Hepatocyte Growth Factor - metabolism; Humans; I-kappa B Kinase - metabolism; Male; MAP Kinase Kinase 3 - metabolism; MAP Kinase Kinase 6; MAP Kinase Kinase Kinases - metabolism; MAP Kinase Signaling System; Neoplasms - metabolism; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-met - metabolism; Proto-Oncogene Proteins pp60(c-src) - metabolism; rac1 GTP-Binding Protein - metabolism; src Homology Domains
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M807497200

Scatter factor (SF) (hepatocyte growth factor) is a pleiotrophic cytokine that accumulates in tumors, where it may induce invasion, angiogenesis, and chemoresistance. We have studied the mechanisms by which SF and its receptor (c-Met) protect cells against the DNA-damaging agent adriamycin (ADR) as a model for chemoresistance of SF/c-Met-overexpressing tumors. Previous studies identified a phosphatidylinositol 3-kinase/c-Akt/Pak1/NF-κB cell survival pathway in DU-145 prostate cancer and Madin-Darby canine kidney epithelial cells. Here we studied Src signaling pathways involved in SF cell protection. Src enhanced basal and SF stimulated NF-κB activity and SF protection against ADR, in a manner dependent upon its kinase and Src homology 3 domains; and endogenous Src was required for SF stimulation of NF-κB activity and cell protection. The ability of Src to enhance SF stimulation of NF-κB activity was due, in part, to its ability to stimulate Akt and IκB kinase activity; and Src-mediated stimulation of NF-κB was due, in part, to a Rac1/MKK3/6/p38 pathway and was Akt-dependent. SF caused the activation of Src and the Rac1 effector Pak1. Furthermore, SF induced activating phosphorylations of MKK3, MKK6, and p38 within the c-Met signalsome in an Src-dependent manner. The NF-κB-inducing kinase was found to act downstream of TAK1 (transforming growth factor-β-activated kinase 1) as a mediator of SF- and Src-stimulated NF-κB activity. Finally, the Src/Rac1/MKK3/6/p38 and Src/TAK1/NF-κB-inducing kinase pathways exhibited cross-talk at the level of MKK3. These findings delineate some novel signaling pathways for SF-mediated resistance to ADR.