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Intrinsic protein disorder in oncogenic KRAS signaling

Abstract

How Ras, and in particular its most abundant oncogenic isoform K-Ras4B, is activated and signals in proliferating cells, poses some of the most challenging questions in cancer cell biology. In this paper, we ask how intrinsically disordered regions in K-Ras4B and its effectors help promote proliferative signaling. Conformational disorder allows spanning long distances, supports hinge motions, promotes anchoring in membranes, permits segments to fulfil multiple roles, and broadly is crucial for activation mechanisms and intensified oncogenic signaling. Here, we provide an overview illustrating some of the key mechanisms through which conformational disorder can promote oncogenesis, with K-Ras4B signaling serving as an example. We discuss (1) GTP-bound KRas4B activation through membrane attachment; (2) how farnesylation and palmitoylation can promote isoform functional specificity; (3) calmodulin binding and PI3K activation; (4) how Ras activates its RASSF5 cofactor, thereby stimulating signaling of the Hippo pathway and repressing proliferation; and (5) how intrinsically disordered segments in Raf help its attachment to the membrane and activation. Collectively, we provide the first inclusive review of the roles of intrinsic protein disorder in oncogenic Ras-driven signaling. We believe that a broad picture helps to grasp and formulate key mechanisms in Ras cancer biology and assists in therapeutic intervention.

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Acknowledgements

This work has been supported by NIH Grant GM06533 (to DF). This work was supported by National Basic Research Program of China (973 Program) (2015CB910403); National Natural Science Foundation of China (81322046, 81302698, 81473137); Shanghai Rising-Star Program (13QA1402300); Program for New Century Excellent Talents in University (NCET-12-0355); Shanghai Health and Family Planning Commission (20154Y0058) (To JZ). This project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. This research was supported [in part] by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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Nussinov, R., Jang, H., Tsai, CJ. et al. Intrinsic protein disorder in oncogenic KRAS signaling. Cell. Mol. Life Sci. 74, 3245–3261 (2017). https://doi.org/10.1007/s00018-017-2564-3

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Keywords

  • KRAS
  • Calmodulin
  • Plasma membrane
  • Colorectal cancer
  • Lung cancer
  • Pancreatic cancer