Ras and cancer: GTP-dependent K-Ras dimers, the role of calmodulin in KRAS-driven adenocarcinomas, the critical role of oncogenic KRAS in the initiation of cancer through deregulation of the G1 cell cycle, and a new view of Ras isoforms in cancers. We discovered the two major interfaces of GTP-dependent K-Ras dimers (GTP-Dependent K-Ras Dimerization. Muratcioglu S, et al. Structure 23(7): 1325-35, 2015). The first, highly populated beta-sheet dimer interface is at the Switch I and effector binding regions, overlapping Raf's, PI3K's, RalGDS' and additional effectors' binding surfaces. This interface has to be inhibitory to such effectors. The second, helical interface also overlaps some effectors' binding sites. This interface may promote Raf's activation. Our data reveal how Ras self-association can regulate effector binding and activity, and suggest that disruption of the helical dimer interface by drugs may abate Raf's signaling in cancer. We pointed out the overlooked critical role of calmodulin in KRAS-driven adenocarcinomas (The Key Role of Calmodulin in KRAS-Driven Adenocarcinomas. Muratcioglu S, et al. Mol Cancer Res. 13(9): 1265-73, 2015). Calmodulin (CaM) selectively binds to GTP-bound K-Ras4B; but not to its isoforms. Cell proliferation and growth require the MAPK (Ras/Raf/MEK/ERK) and PI3Kalpha/Akt pathways. We proposed that Ca2+/CaM promote PI3K/Akt signaling, and suggest how. Ca2+/CaM involvement may explain puzzling observations like the elevated calcium levels in adenocarcinomas. We hypothesized that CaM recruits and helps activate PI3K at the membrane, and that this is the likely reason for Ca2+/CaM-dependence in adenocarcinomas. CaM can contribute to initiation/progression of ductal (pancreatic, colorectal, lung) cancers via both PI3Kalpha/Akt and Raf/MEK/ERK pathways. Blocking the K-Ras/MAPK pathway and CaM/PI3Kalpha binding in a K-Ras4B/CaM/PI3Kalpha trimer could be a promising adenocarcinoma-specific therapeutic strategy. We further illustrated the critical role of oncogenic KRAS in the initiation of cancer through deregulation of the G1 cell cycle (Principles of K-Ras effector organization and the role of oncogenic K-Ras in cancer initiation through G1 cell cycle deregulation. Nussinov R, et al. Expert Rev Proteomics 50(6): 669-82, 2015). We also proposed a new view of Ras isoforms in cancers (A New View of Ras Isoforms in Cancers. Nussinov R, et al. Cancer Res. 2016 Jan 1;76(1):18-23). We proposed that small GTPase K-Ras4A have a single state or two states, one resembling K-Ras4B and the other N-Ras. A recent study of K-Ras4A made the remarkable observation that even in the absence of the palmitoyl K-Ras4A can be active at the plasma membrane. Importantly, this suggests that K-Ras4A may exist in two distinct signaling states. In state 1 K-Ras4A is only farnesylated, like K-Ras4B; in state 2 farnesylated and palmitoylated, like N-Ras. The K-Ras4A hypervariable region (HVR) sequence is positively charged, in-between K-Ras4B and N-Ras. Taken together, this raises the possibility that the farnesylated but nonpalmitoylated state 1, like K-Ras4B, binds calmodulin and is associated with colorectal and other adenocarcinomas like lung cancer and PDAC (pancreatic ductal adenocarcinoma). On the other hand, state 2 may be associated with melanoma and other cancers where N-Ras is a major contributor, such as acute myeloid leukemia (AML). Importantly, H-Ras has two - single and double - palmitoylated states that may also serve distinct functional roles. The multiple signaling states of palmitoylated Ras isoforms question the completeness of small GTPase Ras isoform statistics in different cancer types and call for reevaluation of concepts and protocols. They may also call for reconsideration of oncogenic Ras therapeutics. Additionally, we addressed the interaction of Ras with the membrane which is required for its activation and how oncogenic mutations on KRas would affect its behavior (e.g. GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase KRAS4B, Exposing the Effector Binding Site, Lu S, et al. J Biol Chem. 290(48): 28887-900, 2015) and Mechanisms of Membrane Binding of Small GTPase K-Ras4B Farnesylated Hypervariable Region. Jang H, et al. J Biol Chem. 2015) and more. Our work benefits from our collaborations with experimental groups, including structural groups, NMR and crystallography. We are fortunate to have these outstanding collaborations. We have further extended this work to work out the role of the cysteine-rich domain (CRD) of Raf in Raf-Ras interaction, and have been exploring signaling specificity of oncogenic Ras isoforms at the membrane, and the mechanism of activation of PI3K lipid kinase, which despite its important role in cancer, to date has still been a mystery.

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National Cancer Institute (NCI)
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Jang, Hyunbum; Muratcioglu, Serena; Gursoy, Attila et al. (2016) Membrane-associated Ras dimers are isoform-specific: K-Ras dimers differ from H-Ras dimers. Biochem J 473:1719-32
Lu, Shaoyong; Jang, Hyunbum; Nussinov, Ruth et al. (2016) The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B. Sci Rep 6:21949
Baram, Michal; Atsmon-Raz, Yoav; Ma, Buyong et al. (2016) Amylin-A? oligomers at atomic resolution using molecular dynamics simulations: a link between Type 2 diabetes and Alzheimer's disease. Phys Chem Chem Phys 18:2330-8
Nussinov, Ruth; Muratcioglu, Serena; Tsai, Chung-Jung et al. (2016) K-Ras4B/calmodulin/PI3K?: A promising new adenocarcinoma-specific drug target? Expert Opin Ther Targets 20:831-42
Guven-Maiorov, Emine; Keskin, Ozlem; Gursoy, Attila et al. (2016) TRAF3 signaling: Competitive binding and evolvability of adaptive viral molecular mimicry. Biochim Biophys Acta 1860:2646-55
Datta, Siddhartha A K; Clark, Patrick K; Fan, Lixin et al. (2016) Dimerization of the SP1 Region of HIV-1 Gag Induces a Helical Conformation and Association into Helical Bundles: Implications for Particle Assembly. J Virol 90:1773-87
Lu, Shaoyong; Jang, Hyunbum; Gu, Shuo et al. (2016) Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view. Chem Soc Rev 45:4929-52
Jang, Hyunbum; Banerjee, Avik; Chavan, Tanmay S et al. (2016) The higher level of complexity of K-Ras4B activation at the membrane. FASEB J 30:1643-55
Chakrabarti, Mayukh; Jang, Hyunbum; Nussinov, Ruth (2016) Comparison of the Conformations of KRAS Isoforms, K-Ras4A and K-Ras4B, Points to Similarities and Significant Differences. J Phys Chem B 120:667-79
Xu, Liang; Nussinov, Ruth; Ma, Buyong (2016) Allosteric stabilization of the amyloid-? peptide hairpin by the fluctuating N-terminal. Chem Commun (Camb) 52:1733-6

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