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Vol. 15, Issue 7, 3106-3113, July 2004

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Ribosomal S6 Kinase as a Mediator of Keratinocyte Growth Factor-induced Activation of Akt in Epithelial Cells

Zhong-Zong Pan ^*, Yvan Devaux , and Prabir Ray  

^* Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111; Department of Medicine, Pulmonary, Allergy and Critical Care Medicine and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213

Submitted January 16, 2004; Revised March 31, 2004; Accepted April 13, 2004
Monitoring Editor: Richard Assoian

The keratinocyte growth factor receptor (KGFR) is a member of the fibroblast growth factor receptor (FGFR) superfamily. The proximal signaling molecules of FGFRs are much less characterized compared with other growth factor receptors. Using the yeast two-hybrid assay, we have identified ribosomal S6 kinase (RSK) to be a protein that associates with the cytoplasmic domain of the KGFR. The RSK family of kinases controls multiple cellular processes, and our studies for the first time show association between the KGFR and RSK. Using a lung-specific inducible transgenic system we have recently demonstrated protective effects of KGF on the lung epithelium and have demonstrated KGF-induced activation of the prosurvival Akt pathway both in vivo and in vitro. Here we show that a kinase inactive RSK mutant blocks KGF-induced Akt activation and KGF-mediated inhibition of caspase 3 activation in epithelial cells subjected to oxidative stress. It was recently shown that RSK2 recruits PDK1, the kinase responsible for both Akt and RSK activation. When viewed collectively, it appears that the association between the KGFR and RSK plays an important role in KGF-induced Akt activation and consequently in the protective effects of KGF on epithelial cells.

Corresponding author. E-mail address: rayp{at}pitt.edu.

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