Kinase Suppressor of Ras 1 (KSR1) Regulates PGC1α and Estrogen-Related Receptor α To Promote Oncogenic Ras-Dependent Anchorage-Independent Growth

Kinase suppressor of ras 1 (KSR1) is a molecular scaffold of the Raf/MEK/extracellular signal-regulated kinase (ERK) cascade that enhances oncogenic Ras signaling. Here we show KSR1-dependent, but ERK-independent, regulation of metabolic capacity is mediated through the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1 alpha) and estrogen-related receptor alpha (ERR alpha). This KSR1-regulated pathway is essential for the transformation of cells by oncogenic Ras. In mouse embryo fibroblasts (MEFs) expressing H-Ras(V12), ectopic PGC1 alpha was sufficient to rescue ERR alpha expression, metabolic capacity, and anchorage-independent growth in the absence of KSR1. The ability of PGC1 alpha to promote anchorage-independent growth required interaction with ERR alpha, and treatment with an inhibitor of ERR alpha impeded anchorage-independent growth. In contrast to PGC1 alpha, the expression of constitutively active ERR alpha (CA-ERR alpha) was sufficient to enhance metabolic capacity but not anchorage-independent growth in the absence of KSR1. These data reveal KSR1-dependent control of PGC1 alpha- and ERR alpha-dependent pathways that are necessary and sufficient for signaling by oncogenic H-Ras(V12) to regulate metabolism and anchorage-independent growth, providing novel targets for therapeutic intervention.