Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2009, PMID: 19047046

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

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

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-kappaB 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-kappaB 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-kappaB activity and cell protection. The ability of Src to enhance SF stimulation of NF-kappaB activity was due, in part, to its ability to stimulate Akt and IkappaB kinase activity; and Src-mediated stimulation of NF-kappaB 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-kappaB-inducing kinase was found to act downstream of TAK1 (transforming growth factor-beta-activated kinase 1) as a mediator of SF- and Src-stimulated NF-kappaB activity. Finally, the Src/Rac1/MKK3/6/p38 and Src/TAK1/NF-kappaB-inducing kinase pathways exhibited cross-talk at the level of MKK3. These findings delineate some novel signaling pathways for SF-mediated resistance to ADR.

Diseases/Pathways annotated by Medline MESH: MAP Kinase Signaling System, Neoplasms
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Text Mining Data

Src → NF-kappaB: " Src enhanced basal and SF stimulated NF-kappaB 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-kappaB activity and cell protection "

NF-kappaB ⊣ IkappaB kinase: " The ability of Src to enhance SF stimulation of NF-kappaB activity was due, in part, to its ability to stimulate Akt and IkappaB kinase activity ; and Src mediated stimulation of NF-kappaB was due , in part, to a Rac1/MKK3/6/p38 pathway and was Akt dependent "

NF-kappaB ⊣ Akt: " The ability of Src to enhance SF stimulation of NF-kappaB activity was due, in part, to its ability to stimulate Akt and IkappaB kinase activity ; and Src mediated stimulation of NF-kappaB was due , in part, to a Rac1/MKK3/6/p38 pathway and was Akt dependent "

NF-kappaB → Src: " The ability of Src to enhance SF stimulation of NF-kappaB activity was due, in part, to its ability to stimulate Akt and IkappaB kinase activity ; and Src mediated stimulation of NF-kappaB was due, in part, to a Rac1/MKK3/6/p38 pathway and was Akt dependent "

NF-kappaB → Src: " The NF-kappaB inducing kinase was found to act downstream of TAK1 ( transforming growth factor-beta activated kinase 1 ) as a mediator of SF- and Src stimulated NF-kappaB activity "

Manually curated Databases

No curated data.