Intrinsic protein disorder in oncogenic KRAS signaling

Ruth Nussinov*, Hyunbum Jang, Chung Jung Tsai, Tsung Jen Liao, Shuai Li, David Fushman, Jian Zhang

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


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.

Original languageEnglish
Pages (from-to)3245-3261
Number of pages17
JournalCellular and Molecular Life Sciences
Issue number17
StatePublished - 1 Sep 2017


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


Dive into the research topics of 'Intrinsic protein disorder in oncogenic KRAS signaling'. Together they form a unique fingerprint.

Cite this