Nussinov Ruth, Muratcioglu Serena, Tsai Chung-Jung, Jang Hyunbum, Gursoy Attila, Keskin Ozlem
Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, NCI at Frederick, Frederick, Maryland. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey.
Mol Cancer Res. 2015 Sep;13(9):1265-73. doi: 10.1158/1541-7786.MCR-15-0165. Epub 2015 Jun 17.
KRAS4B is a highly oncogenic splice variant of the KRAS isoform. It is the only isoform associated with initiation of adenocarcinomas. Insight into why and how KRAS4B can mediate ductal adenocarcinomas, particularly of the pancreas, is vastly important for its therapeutics. Here we point out the overlooked critical role of calmodulin (CaM). Calmodulin selectively binds to GTP-bound K-Ras4B; but not to other Ras isoforms. Cell proliferation and growth require the MAPK (Raf/MEK/ERK) and PI3K/Akt pathways. We propose that Ca(2+)/calmodulin promote PI3Kα/Akt signaling, and suggest how. The elevated calcium levels clinically observed in adenocarcinomas may explain calmodulin's involvement in recruiting and stimulating PI3Kα through interaction with its n/cSH2 domains as well as K-Ras4B; importantly, it also explains why K-Ras4B specifically is a key player in ductal carcinomas, such as pancreatic (PDAC), colorectal (CRC), and lung cancers. We hypothesize that calmodulin recruits and helps activate PI3Kα at the membrane, and that this is the likely reason for Ca(2+)/calmodulin dependence in adenocarcinomas. Calmodulin can contribute to initiation/progression of ductal cancers via both PI3Kα/Akt and Raf/MEK/ERK pathways. Blocking the K-Ras4B/MAPK pathway and calmodulin/PI3Kα binding in a K-Ras4B/calmodulin/PI3Kα trimer could be a promising adenocarcinoma-specific therapeutic strategy.
KRAS4B是KRAS亚型的一种高度致癌性剪接变体。它是唯一与腺癌起始相关的亚型。深入了解KRAS4B为何以及如何介导导管腺癌，尤其是胰腺癌，对其治疗具有极其重要的意义。在此我们指出钙调蛋白（CaM）被忽视的关键作用。钙调蛋白选择性地与结合GTP的K-Ras4B结合，而不与其他Ras亚型结合。细胞增殖和生长需要MAPK（Raf/MEK/ERK）和PI3K/Akt信号通路。我们提出Ca(2+)/钙调蛋白促进PI3Kα/Akt信号传导，并说明了其作用方式。腺癌临床观察到的钙水平升高可能解释了钙调蛋白通过与其n/cSH2结构域以及K-Ras4B相互作用参与募集和刺激PI3Kα；重要的是，这也解释了为什么K-Ras4B特别是导管癌（如胰腺癌（PDAC）、结直肠癌（CRC）和肺癌）中的关键因素。我们假设钙调蛋白在细胞膜上募集并帮助激活PI3Kα，这可能是腺癌中Ca(2+)/钙调蛋白依赖性的原因。钙调蛋白可通过PI3Kα/Akt和Raf/MEK/ERK信号通路促进导管癌的起始/进展。阻断K-Ras4B/MAPK信号通路以及K-Ras4B/钙调蛋白/PI3Kα三聚体中的钙调蛋白/PI3Kα结合可能是一种有前景的腺癌特异性治疗策略。
