title: The mystery of oncogenic KRAS: Lessons from studying its wild-type counter part.
abstract: Using conditional knock-in mouse models, we and others have shown that despite the very high sequence identity between Nras and Kras proteins, oncogenic Kras displays a much stronger leukemogenic activity than oncogenic Nras in vivo. In this manuscript, we will summarize our recent work of characterizing wild-type Kras function in adult hematopoiesis and in oncogenic Kras-induced leukemogenesis. We attribute the strong leukemogenic activity of oncogenic Kras to 2 unique aspects of Kras signaling. First, Kras is required in mediating cell type- and cytokine-specific ERK1/2 signaling. Second, oncogenic Kras, but not oncogenic Nras, induces hyperactivation of wild-type Ras, which significantly enhances Ras signaling in vivo. We will also discuss a possible mechanism that mediates oncogenic Kras-evoked hyperactivation of wild-type Ras and a potential approach to down-regulate oncogenic Kras signaling.
authors.affiliation: a McArdle Laboratory for Cancer Research, University of Wisconsin-Madison , Madison , WI , USA.|b Institute of Physiology, National Yang-Ming University , Taipei City , Taiwan.
authors.forename: Yuan-I
authors.initials: YI
authors.lastname: Chang
authors.affiliation: a McArdle Laboratory for Cancer Research, University of Wisconsin-Madison , Madison , WI , USA.|c Faculty of Science , Department of Biology, Mahidol University , Thailand.
authors.forename: Alisa
authors.initials: A
authors.lastname: Damnernsawad
authors.affiliation: a McArdle Laboratory for Cancer Research, University of Wisconsin-Madison , Madison , WI , USA.
authors.forename: Guangyao
authors.initials: G
authors.lastname: Kong
authors.affiliation: a McArdle Laboratory for Cancer Research, University of Wisconsin-Madison , Madison , WI , USA.
authors.forename: Xiaona
authors.initials: X
authors.lastname: You
authors.affiliation: d Blood Research Institute, Blood Center of Wisconsin , Milwaukee , WI , USA.
authors.forename: Demin
authors.initials: D
authors.lastname: Wang
authors.affiliation: a McArdle Laboratory for Cancer Research, University of Wisconsin-Madison , Madison , WI , USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D009154:Mutation
keywords: SOS1; leukemogenesis; oncogenic Kras; oncogenic Nras; wild-type Kras