Principles of K-Ras effector organization and the role of oncogenic K-Ras in cancer initiation through G1 cell cycle deregulation.
Illustrated here is the critical role of oncogenic KRAS in the initiation of cancer through deregulation of the G1 cell cycle, and elements and scenarios taking place under physiological conditions and in KRAS-driven cancer. Raf, PI3K and RalGDS are major K-Ras effectors. They bind at the same Ras site. What decides the cell selection among them? This temporal and spatial decision is critical since in some cellular context the outcome of their signaling pathways may oppose each other. Key among them is the concentration of calcium/calmodulin, negative feedback loops, where a downstream member of the pathway inhibits its upstream activator and cross-inhibition, where inhibition entails blocking another pathway. These three elements, in addition to spatial restrictions by K-Ras-membrane interactions, are not independent; they integrate to provide blueprints for cell decisions. Importantly, elucidation of signaling requires not only K-Ras binary interactions; but the structures and dynamics of its multiprotein complexes.
a Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Cancer and Inflammation Program , National Cancer Institute , Frederick , MD , USA.|b Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine , Aviv University , Tel Aviv , Israel.
Ruth
R
Nussinov
a Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Cancer and Inflammation Program , National Cancer Institute , Frederick , MD , USA.
Chung-Jung
CJ
Tsai
c Departments of Chemical & Biological Engineering , Koc University , Istanbul , Turkey.
Serena
S
Muratcioglu
a Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Cancer and Inflammation Program , National Cancer Institute , Frederick , MD , USA.
Hyunbum
H
Jang
d Computer Engineering , Koc University , Istanbul , Turkey.
Attila
A
Gursoy
c Departments of Chemical & Biological Engineering , Koc University , Istanbul , Turkey.
Ozlem
O
Keskin
D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D048490:raf Kinases / Q000378:metabolism; D020726:ral Guanine Nucleotide Exchange Factor / Q000378:metabolism
C117307:KRAS protein, human; D020726:ral Guanine Nucleotide Exchange Factor; D019869:Phosphatidylinositol 3-Kinases; D048490:raf Kinases; D016283:Proto-Oncogene Proteins p21(ras)
K-Ras; K-Ras4B; KRAS4B; PI3K; Raf; RalGDS; Ras effectors; Ras isoforms; calmodulin; cell cycle; lung cancer; pancreatic cancer