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Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling

Abstract

Activating mutations in genes of the Ras-mitogen-activated protein kinase (MAPK) pathway occur in approximately 30% of all human cancers; however, mutation of Ras alone is rarely sufficient to induce tumour development. Scribble is a polarity regulator recently isolated from a Drosophila screen for events that cooperate with Ras mutation to promote tumour progression and cell invasion. In mammals, Scribble regulates directed cell migration and wound healing in vivo; however, no role has been identified for mammalian Scribble in oncogenic transformation. Here we show that in human epithelial cells expressing oncogenic Ras or Raf, loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system. Further, we show that the mechanism by which this occurs is in the regulation of MAPK signalling by Scribble. The suppression of MAPK signalling is a highly conserved function of Scribble as it also prevents Raf-mediated defects in Drosophila wing development. Our data identify Scribble as an important mediator of MAPK signalling and provide a molecular basis for the observation that Scribble expression is decreased in many invasive human cancers.

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Acknowledgements

We thank Dr David Tuveson, Dr Christopher Counter and Dr Michael Olson for providing key reagents for this study, Dr Anthony Brumby, Peter Burke, Linda Parsons and Karen Goulding for constructing fly strains and preparing and photographing the Drosophila wings and to the microscopy and FACS core facilities at the Peter MacCallum Cancer Centre for their invaluable assistance. Thanks to Dr Sarah Russell and Dr Anthony Brumby for discussions and comments on the paper. This study was supported by grants from the Association for International Cancer Research (AICR, UK) and the Cancer Council Victoria (CCV). HER is an NH&MRC Senior Research Fellow. POH is an RD Wright Fellow of the NH&MRC. LED and IAE were supported by Cancer Council Victoria Postgraduate Cancer Research Scholarships.

Contributions: LED designed, performed and analysed experiments and wrote the paper. IAE performed and analysed experiments. CLK performed and analysed experiments. KMK performed experiments. HER designed and performed and analysed experiments. POH designed experiments and wrote the paper.

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Correspondence to P O Humbert.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Dow, L., Elsum, I., King, C. et al. Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling. Oncogene 27, 5988–6001 (2008). https://doi.org/10.1038/onc.2008.219

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