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

Content Provider	Journal of Biological Chemistry (JBC)
Author	Fan, Saijun Meng, Qinghui Laterra, John J. Rosen, Eliot M.
Abstract	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.
Related Links	http://www.jbc.org/content/284/12/7561.abstract
Ending Page	7577
Starting Page	7561
Page Count	17
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	12
Volume Number	284
DOI	10.1074/jbc.M807497200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2009-03-20
Access Restriction	Open
Subject Keyword	Mechanisms of Signal Transduction
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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