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

Oncogene volume 36, pages 2619–2627 (2017)Cite this article

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Abstract

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 Ca2+-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.

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Acknowledgements

This work was supported by the Fay Fuller Foundation, Project Grant (1004695) and Senior Research Fellowships (508098 and 1042589) from the National Health and Medical Research Council of Australia (to SMP), NIH 1R01HL092544 (to LVP), University of Adelaide Graduate Research and Research Training Scheme Scholarships (to WZ), an Australian Postgraduate Award and Royal Adelaide Hospital (RAH) Dawes Scholarship (to KEJ) and a RAH Research Foundation Early Career Fellowship (to MRP). We thank J Downward (Imperial Cancer Research Fund, London) and R Parton (Institute for Molecular Bioscience, Brisbane) for providing the H- and KRas plasmids, respectively, and M Okabe (Osaka University) for providing the pCX-EGFP plasmid. Some of the data shown are based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.

Author contributions

Conception and design by W Zhu, GL Gliddon, K Jarman and SM Pitson. Development of methodology by W Zhu, GL Gliddon, MR Pitman and SM Pitson. Acquisition of data (provided animals, acquired and managed patients, provided facilities and so on.) by W Zhu, GL Gliddon, K Jarman, PAB Moretti, T Tin, LV Parise, JM Woodcock, JA Powell and A Ruszkiewicz. Analysis and interpretation of data (for example, statistical analysis, biostatistics and computational analysis) by W Zhu, GL Gliddon, K Jarman, JM Woodcock, JA Powell, A Ruszkiewicz, MR Pitman and SM Pitson. Writing, review and/or revision of the manuscript by W Zhu, GL Gliddon, LV Parise, A Ruszkiewicz, JM Woodcock, MR Pitman and SM Pitson. Administrative, technical or material support (that is, reporting or organizing data and constructing databases) by W Zhu, GL Gliddon, K Jarman and SM Pitson. Study supervision by MR Pitman, GL Gliddon and SM Pitson.

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Author notes

  1. B L Gliddon and S M Pitson: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia

    W Zhu, B L Gliddon, K E Jarman, P A B Moretti, T Tin, J M Woodcock, J A Powell, A Ruszkiewicz, M R Pitman & S M Pitson

  2. School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia

    W Zhu, K E Jarman & S M Pitson

  3. Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA

    L V Parise

  4. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    J A Powell & S M Pitson

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Correspondence to S M Pitson.

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LV Parise is a cofounder of Reveris Therapeutics.

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Zhu, W., Gliddon, B., Jarman, K. et al. CIB1 contributes to oncogenic signalling by Ras via modulating the subcellular localisation of sphingosine kinase 1. Oncogene 36, 2619–2627 (2017). https://doi.org/10.1038/onc.2016.428

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