title: CIB1 contributes to oncogenic signalling by Ras via modulating the subcellular localisation of sphingosine kinase 1.
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.
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: W
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: B L
authors.initials: BL
authors.lastname: Gliddon
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: K E
authors.initials: KE
authors.lastname: Jarman
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: P A B
authors.initials: PAB
authors.lastname: Moretti
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Tin
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: L V
authors.initials: LV
authors.lastname: Parise
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: J M
authors.initials: JM
authors.lastname: Woodcock
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Powell
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Ruszkiewicz
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: M R
authors.initials: MR
authors.lastname: Pitman
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: S M
authors.initials: SM
authors.lastname: Pitson
mesh_terms: D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000235:genetics*; D000099157:Sphingosine Kinase
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D016283:Proto-Oncogene Proteins p21(ras); D000099157:Sphingosine Kinase; C109198:CIB1 protein, human; C117307:KRAS protein, human; C501009:HRAS protein, human