Role of Src signal transduction pathways in scatter factor-mediated cellular protection

Saijun Fan, Qinghui Meng, John J Laterra, Eliot M. Rosen

Research output: Contribution to journalArticle

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 IaB 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.

Original languageEnglish (US)
Pages (from-to)7561-7577
Number of pages17
JournalJournal of Biological Chemistry
Volume284
Issue number12
DOIs
StatePublished - Mar 20 2009

Fingerprint

Signal transduction
Hepatocyte Growth Factor
Signal Transduction
Phosphotransferases
Doxorubicin
Cytoprotection
Tumors
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-met
Phosphorylation
Madin Darby Canine Kidney Cells
src Homology Domains
src-Family Kinases
Transforming Growth Factors
Neoplasms
Prostatic Neoplasms
Cell Survival
B-Lymphocytes
Epithelial Cells
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Role of Src signal transduction pathways in scatter factor-mediated cellular protection. / Fan, Saijun; Meng, Qinghui; Laterra, John J; Rosen, Eliot M.

In: Journal of Biological Chemistry, Vol. 284, No. 12, 20.03.2009, p. 7561-7577.

Research output: Contribution to journalArticle

Fan, Saijun ; Meng, Qinghui ; Laterra, John J ; Rosen, Eliot M. / Role of Src signal transduction pathways in scatter factor-mediated cellular protection. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 12. pp. 7561-7577.
@article{def14e960c8744589637fb828df164b2,
title = "Role of Src signal transduction pathways in scatter factor-mediated cellular protection",
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 IaB 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.",
author = "Saijun Fan and Qinghui Meng and Laterra, {John J} and Rosen, {Eliot M.}",
year = "2009",
month = "3",
day = "20",
doi = "10.1074/jbc.M807497200",
language = "English (US)",
volume = "284",
pages = "7561--7577",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "12",

}

TY - JOUR

T1 - Role of Src signal transduction pathways in scatter factor-mediated cellular protection

AU - Fan, Saijun

AU - Meng, Qinghui

AU - Laterra, John J

AU - Rosen, Eliot M.

PY - 2009/3/20

Y1 - 2009/3/20

N2 - 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 IaB 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.

AB - 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 IaB 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.

UR - http://www.scopus.com/inward/record.url?scp=65549146416&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65549146416&partnerID=8YFLogxK

U2 - 10.1074/jbc.M807497200

DO - 10.1074/jbc.M807497200

M3 - Article

C2 - 19047046

AN - SCOPUS:65549146416

VL - 284

SP - 7561

EP - 7577

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 12

ER -