1. ¹Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
2. ²Department of Neurology, The Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD, USA

Correspondence: Dr EM Rosen, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Box 571469, Washington, DC 20057-1469, USA. E-mail: emr36@georgetown.edu

Received 27 April 2006; Revised 30 October 2006; Accepted 14 November 2006; Published online 12 February 2007.

Abstract

Scatter factor (SF) (hepatocyte growth factor) is a pleiotrophic cytokine that accumulates within tumors in vivo and protects tumor cells against cytotoxicity and apoptosis due to DNA damaging agents in vitro. Previous studies have established that SF-mediated cell protection involves antiapoptotic signaling from its receptor (c-Met) to PI3 kinase c-Akt Pak1 (p21-activated kinase -1) NF-B (nuclear factor-kappa B). Here, we found that Ras proteins (H-Ras and R-Ras) enhance SF-mediated activation of NF-B and protection of DU-145 and MDCK (Madin–Darby canine kidney) cells against the topoisomerase II inhibitor adriamycin. Studies of Ras effector loop mutants and their downstream effectors suggest that Ras/PI3 kinase and Ras/Raf1 pathways contribute to SF stimulation of NF-B signaling and cell protection. Further studies revealed that Raf1 positively regulates the ability of SF to stimulate NF-B activity and cell protection. The ability of Raf1 to stimulate NF-B activity was not due to the classical Raf1 MEK1/2 ERK1/2 pathway. However, we found that a MEK3/6 p38 pathway contributes to SF-mediated activation of NF-B. In contrast, RalA, a target of the Ras/RalGDS pathway negatively regulated the ability of SF to stimulate NF-B activity and cell protection. Ras, Raf1 and RalA modulate SF stimulation of NF-B activity, in part, by regulating IB kinase (IKK)- kinase activity. These findings suggest that Ras/Raf1/RalA pathways may converge to modulate NF-B activation and SF-mediated survival signaling at the IKK complex and/or a kinase upstream of this complex.