CIB1 contributes to oncogenic signalling by Ras via modulating the subcellular localisation of sphingosine kinase 1

• Published in: Oncogene Vol. 36; no. 18; pp. 2619 - 2627
• Main Authors: Zhu, W, Gliddon, B L, Jarman, K E, Moretti, P A B, Tin, T, Parise, L V, Woodcock, J M, Powell, J A, Ruszkiewicz, A, Pitman, M R, Pitson, S M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.05.2017; Nature Publishing Group
• Subjects: 14/19; 631/67/395; 631/80/86/2365; 82/80; 96/95; Angiogenesis; Apoptosis; Binding proteins; Binding sites; Blood platelets; Calcium - metabolism; Calcium-binding protein; Calcium-Binding Proteins - genetics; Cancer; Carcinogenesis; Carcinogenesis - genetics; Cell Biology; Cell Line, Tumor; Cell Membrane - genetics; Cell Survival; Cellular signal transduction; Chemical properties; Cytoplasm; Ectopic expression; Enzymatic activity; Gene Expression Regulation, Neoplastic - genetics; Genetic transformation; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; Localization; Medicine; Medicine & Public Health; Neoplasms - genetics; Neoplasms - pathology; Oncogenes; Oncology; Overexpression; Phosphotransferases (Alcohol Group Acceptor) - genetics; Physiological aspects; Proteins; Proto-Oncogene Proteins p21(ras) - biosynthesis; Proto-Oncogene Proteins p21(ras) - genetics; Ras protein; short-communication; Sphingosine; Sphingosine kinase; Tumorigenesis; Australia
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.428

CIB1 (calcium and integrin binding protein 1) is a small intracellular protein with numerous interacting partners, and hence has been implicated in various cellular functions. Recent studies have revealed emerging roles of CIB1 in regulating cancer cell survival and angiogenesis, although the mechanisms involved have remained largely undefined. In investigating the oncogenic function of CIB1, we initially found that CIB1 is widely up-regulated across a diverse range of cancers, with this upregulation frequently correlating with oncogenic mutations of KRas. Consistent with this, we found that ectopic expression of oncogenic KRas and HRas in cells resulted in elevated CIB1 expression. We previously described the Ca 2+ -myristoyl switch function of CIB1, and its ability to facilitate agonist-induced plasma membrane localisation of sphingosine kinase 1 (SK1), a location where SK1 is known to elicit oncogenic signalling. Thus, we examined the role this may play in oncogenesis. Consistent with these findings, we demonstrated here that over-expression of CIB1 by itself is sufficient to drive localisation of SK1 to the plasma membrane and enhance the membrane-associated enzymatic activity of SK1, as well as its oncogenic signalling. We subsequently demonstrated that elevated levels of CIB1 resulted in full neoplastic transformation, in a manner dependent on SK1. In agreement with our previous findings that SK1 is a downstream mediator of oncogenic signalling by Ras, we found that targeting CIB1 also inhibited neoplastic growth of cells induced by oncogenic Ras, suggesting an important pro-tumorigenic role for CIB1. Thus, we have demonstrated for the first time a role for CIB1 in neoplastic transformation, and revealed a novel mechanism facilitating oncogenic signalling by Ras and SK1.