Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice.
In Drosophila and Caenorhabditis elegans, kinase suppressor of ras (KSR) positively modulates Ras/Raf-mitogen-activated protein kinase (MAPK) signaling. The precise signaling mechanism of mammalian KSR1 and its role in Ras-mediated transformation, however, remain uncertain. To gain insight into KSR1 function in vivo, we generated mice homozygous null for KSR1. ksr1-/- mice are viable and without major developmental defects. However, an unusual disorganized hair follicle phenotype manifest in epidermal growth factor receptor knockout mice is recapitulated in ksr1-/- mice, providing genetic support for the notion that epidermal growth factor receptor, Ras, and KSR1 are on the same signaling pathway in mammals. Furthermore, ksr1-/- mice allow for the definition of KSR1-dependent and -independent mechanisms of c-Raf-1 activation. In embryonic fibroblasts, epidermal growth factor and 12-O-tetradecanoylphorbol-13-acetate activated the MAPK cascade to a similar extent, yet only c-Raf-1 activation by epidermal growth factor depended on KSR1. Moreover, whereas the genesis of polyomavirus middle T antigen (MT)-driven mammary cancer appears independent of KSR1, KSR1 is obligate for v-Ha-ras-mediated skin tumor formation. The growth of MT-driven mammary tumor was moderately slowed in ksr1-/- mice, however, consistent with a decreased rate of proliferation of ksr1-/- cells (T cells and embryonic fibroblasts). Nonetheless, all ksr1-/- animals succumbed to mammary cancer. In contrast, papilloma formation in Tg.AC mice, resulting from skin-specific v-Ha-ras expression, was completely abrogated in the ksr1-/- background. Hence, MT-driven mammary tumor genesis, which is signaled through src and phosphatidylinositol 3'-kinase, appears KSR1 independent, whereas v-Ha-ras-mediated skin cancer, signaled through the Raf-1/MAPK cascade, requires KSR1. These results suggest KSR1 may represent a therapeutic target for Ras/MAPK signaling of human tumorigenesis.
Lozano
José
J
Laboratory of Signal Transduction, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Xing
Rosie
R
Cai
Zhenzi
Z
Jensen
Heather L
HL
Trempus
Carol
C
Mark
Willie
W
Cannon
Ron
R
Kolesnick
Richard
R
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D011905:Genes, ras / Q000502:physiology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics; D011247:Pregnancy; D011494:Protein Kinases / Q000172:deficiency* / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics; D018631:ras Proteins / Q000502:physiology*
D011494:Protein Kinases; C097199:KSR-1 protein kinase; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins