Intrinsic protein disorder in oncogenic KRAS signaling

• Published in: Cellular and molecular life sciences : CMLS Vol. 74; no. 17; pp. 3245 - 3261
• Main Authors: Nussinov, Ruth, Jang, Hyunbum, Tsai, Chung-Jung, Liao, Tsung-Jen, Li, Shuai, Fushman, David, Zhang, Jian
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.09.2017; Springer Nature B.V
• Subjects: 1-Phosphatidylinositol 3-kinase; Activation; Anchoring; Attachment; Biochemistry; Biology; Biomedical and Life Sciences; Biomedicine; Calcium-binding protein; Calmodulin; Calmodulin - chemistry; Calmodulin - metabolism; Cancer; Cell adhesion & migration; Cell Biology; Colorectal cancer; Effectors; Guanosine triphosphate; Intrinsically Disordered Proteins - chemistry; Intrinsically Disordered Proteins - metabolism; K-Ras protein; Life Sciences; Lipoylation; Membranes; Molecular Dynamics Simulation; Multi-author Review; Neoplasms - metabolism; Neoplasms - pathology; Palmitoylation; Pancreatic cancer; Protein Domains; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Proteins; raf Kinases - chemistry; raf Kinases - metabolism; Raf protein; ras Proteins - chemistry; ras Proteins - metabolism; Segments; Signal Transduction; Signaling; Tumorigenesis; KRAS; Lung cancer; Pancreatic cancer; Calmodulin; Plasma membrane; Colorectal cancer
• ISSN: 1420-682X; 1420-9071; 1420-9071
• DOI: 10.1007/s00018-017-2564-3

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.