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, Chavan TS, Freed BC, Jang H, Khavrutskii L, Freed RN, Dyba MA5, Stefanisko K, Tarasov SG, Gursoy A, Keskin O, Tarasova NI, Gaponenko V, Nussinov R. 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, Tsai C.-J., Jang H, Gursoy A, Keskin O, Nussinov R. 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, Tsai C-J, Muratcioglu S, Jang H, Gursoy A, Keskin O. 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, Tsai C-J, Chakrabarti M, Jang H. Cancer Res. [Epub ahead of print - Dec. 10], 2015). 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, Banerjee A, Jang H, Zhang J, Gaponenko V, Nussinov R. J Biol Chem. 290(48): 28887-900, 2015) and Mechanisms of Membrane Binding of Small GTPase K-Ras4B Farnesylated Hypervariable Region (Jang H, Abraham SJ, Chavan TS, Hitchinson B, Khavrutskii L, Tarasova NI, Nussinov R, Gaponenko V. 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010440-16
Application #
9556285
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Ma, Buyong; Zhao, Jun; Nussinov, Ruth (2016) Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes. Biochim Biophys Acta 1860:2672-81
Xu, Liang; Nussinov, Ruth; Ma, Buyong (2016) Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the ?-synuclein fibrils. Eur J Med Chem 121:841-850
Papaleo, Elena; Saladino, Giorgio; Lambrughi, Matteo et al. (2016) The Role of Protein Loops and Linkers in Conformational Dynamics and Allostery. Chem Rev 116:6391-423
Guven-Maiorov, Emine; Tsai, Chung-Jung; Nussinov, Ruth (2016) Pathogen mimicry of host protein-protein interfaces modulates immunity. Semin Cell Dev Biol :
Lu, Shaoyong; Jang, Hyunbum; Zhang, Jian et al. (2016) Inhibitors of Ras-SOS Interactions. ChemMedChem 11:814-21
Banerjee, Avik; Jang, Hyunbum; Nussinov, Ruth et al. (2016) The disordered hypervariable region and the folded catalytic domain of oncogenic K-Ras4B partner in phospholipid binding. Curr Opin Struct Biol 36:10-7
Xu, Liang; Zheng, Jie; Margittai, Martin et al. (2016) How Does Hyperphopsphorylation Promote Tau Aggregation and Modulate Filament Structure and Stability? ACS Chem Neurosci 7:565-75
Lei, Jiangtao; Qi, Ruxi; Wei, Guanghong et al. (2016) Self-aggregation and coaggregation of the p53 core fragment with its aggregation gatekeeper variant. Phys Chem Chem Phys 18:8098-107
Nussinov, Ruth; Tsai, Chung-Jung; Chakrabarti, Mayukh et al. (2016) A New View of Ras Isoforms in Cancers. Cancer Res 76:18-23
Jang, Hyunbum; Arce, Fernando Teran; Lee, Joon et al. (2016) Computational Methods for Structural and Functional Studies of Alzheimer's Amyloid Ion Channels. Methods Mol Biol 1345:251-68

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