Cellular and Molecular Life Sciences

, Volume 74, Issue 17, pp 3245–3261 | Cite as

Intrinsic protein disorder in oncogenic KRAS signaling

  • Ruth Nussinov
  • Hyunbum Jang
  • Chung-Jung Tsai
  • Tsung-Jen Liao
  • Shuai Li
  • David Fushman
  • Jian Zhang
Multi-author Review

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.

Keywords

KRAS Calmodulin Plasma membrane Colorectal cancer Lung cancer Pancreatic cancer 

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Ruth Nussinov
    • 1
    • 2
  • Hyunbum Jang
    • 1
  • Chung-Jung Tsai
    • 1
  • Tsung-Jen Liao
    • 1
    • 3
  • Shuai Li
    • 4
  • David Fushman
    • 3
  • Jian Zhang
    • 4
  1. 1.Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer ResearchNational Cancer Institute at FrederickFrederickUSA
  2. 2.Department of Human Molecular Genetics and Biochemistry, Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Department of Chemistry and Biochemistry, Center for Biomolecular Structure and OrganizationUniversity of MarylandCollege ParkUSA
  4. 4.Department of Pathophysiology, Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University, School of MedicineShanghaiChina

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