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

Oncogene volume 27, pages 5988–6001 (2008)Cite this article

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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References

  • Abdelilah-Seyfried S, Cox DN, Jan YN . (2003). Bazooka is a permissive factor for the invasive behavior of discs large tumor cells in Drosophila ovarian follicular epithelia. Development 130: 1927–1935.

    Article  CAS  PubMed  Google Scholar 

  • Aguilar-Cordova E, Strange R, Young LJ, Billy HT, Gumerlock PH, Cardiff RD . (1991). Viral Ha-ras mediated mammary tumor progression. Oncogene 6: 1601–1607.

    CAS  PubMed  Google Scholar 

  • Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M et al. (2007). The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 26: 6979–6988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aranda V, Haire T, Nolan ME, Calarco JP, Rosenberg AZ, Fawcett JP et al. (2006). Par6-aPKC uncouples ErbB2 induced disruption of polarized epithelial organization from proliferation control. Nat Cell Biol 8: 1235–1245.

    Article  CAS  PubMed  Google Scholar 

  • Audebert S, Navarro C, Nourry C, Chasserot-Golaz S, Lecine P, Bellaiche Y et al. (2004). Mammalian Scribble forms a tight complex with the betaPIX exchange factor. Curr Biol 14: 987–995.

    Article  CAS  PubMed  Google Scholar 

  • Bilder D, Li M, Perrimon N . (2000). Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289: 113–116.

    Article  CAS  PubMed  Google Scholar 

  • Bilder D, Perrimon N . (2000). Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature 403: 676–680.

    Article  CAS  PubMed  Google Scholar 

  • Brumby AM, Richardson HE . (2003). Scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J 22: 5769–5779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Debnath J, Muthuswamy SK, Brugge JS . (2003). Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30: 256–268.

    Article  CAS  PubMed  Google Scholar 

  • Dhillon AS, Hagan S, Rath O, Kolch W . (2007). MAP kinase signalling pathways in cancer. Oncogene 26: 3279–3290.

    Article  CAS  PubMed  Google Scholar 

  • Dow LE, Brumby AM, Muratore R, Coombe ML, Sedelies KA, Trapani JA et al. (2003). hScrib is a functional homologue of the Drosophila tumour suppressor Scribble. Oncogene 22: 9225–9230.

    Article  CAS  PubMed  Google Scholar 

  • Dow LE, Humbert PO . (2007). Polarity regulators and the control of epithelial architecture, cell migration, and tumorigenesis. Int Rev Cytol 262: 253–302.

    Article  CAS  PubMed  Google Scholar 

  • Dow LE, Kauffman JS, Caddy J, Zarbalis K, Peterson AS, Jane SM et al. (2007). The tumour-suppressor scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge. Oncogene 26: 5692.

    Article  CAS  Google Scholar 

  • Frese KK, Latorre IJ, Chung SH, Caruana G, Bernstein A, Jones SN et al. (2006). Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor suppressor. EMBO J 25: 1406–1417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gardiol D, Kuhne C, Glaunsinger B, Lee SS, Javier R, Banks L . (1999). Oncogenic human papillomavirus E6 proteins target the discs large tumour suppressor for proteasome-mediated degradation. Oncogene 18: 5487–5496.

    Article  CAS  PubMed  Google Scholar 

  • Gardiol D, Zacchi A, Petrera F, Stanta G, Banks L . (2006). Human discs large and scrib are localized at the same regions in colon mucosa and changes in their expression patterns are correlated with loss of tissue architecture during malignant progression. Int J Cancer 119: 1285–1290.

    Article  CAS  PubMed  Google Scholar 

  • Giunciuglio D, Culty M, Fassina G, Masiello L, Melchiori A, Paglialunga G et al. (1995). Invasive phenotype of MCF10A cells overexpressing c-Ha-ras and c-erbB-2 oncogenes. Int J Cancer 63: 815–822.

    Article  CAS  PubMed  Google Scholar 

  • Goode S, Perrimon N . (1997). Inhibition of patterned cell shape change and cell invasion by discs large during Drosophila oogenesis. Genes Dev 11: 2532–2544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Humbert PO, Dow LE, Russell SM . (2006). The Scribble and Par complexes in polarity and migration: friends or foes? Trends Cell Biol 16: 622–630.

    Article  CAS  PubMed  Google Scholar 

  • Joiakim A, Mathieu PA, Palermo C, Gasiewicz TA, Reiners Jr JJ . (2003). The Jun N-terminal kinase inhibitor SP600125 is a ligand and antagonist of the aryl hydrocarbon receptor. Drug Metab Dispos 31: 1279–1282.

    Article  CAS  PubMed  Google Scholar 

  • Kamei Y, Kito K, Takeuchi T, Imai Y, Murase R, Ueda N et al. (2007). Human scribble accumulates in colorectal neoplasia in association with an altered distribution of beta-catenin. Hum Pathol 38: 1273–1281.

    Article  CAS  PubMed  Google Scholar 

  • Kim ES, Kim MS, Moon A . (2004). TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol 25: 1375–1382.

    CAS  PubMed  Google Scholar 

  • Kim ES, Kim MS, Moon A . (2005). Transforming growth factor (TGF)-beta in conjunction with H-ras activation promotes malignant progression of MCF10A breast epithelial cells. Cytokine 29: 84–91.

    Article  CAS  PubMed  Google Scholar 

  • Kim MS, Lee EJ, Kim HR, Moon A . (2003). p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells. Cancer Res 63: 5454–5461.

    CAS  PubMed  Google Scholar 

  • Kiyono T, Hiraiwa A, Fujita M, Hayashi Y, Akiyama T, Ishibashi M . (1997). Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein. Proc Natl Acad Sci USA 94: 11612–11616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lahuna O, Quellari M, Achard C, Nola S, Meduri G, Navarro C et al. (2005). Thyrotropin receptor trafficking relies on the hScrib-betaPIX-GIT1-ARF6 pathway. EMBO J 24: 1364–1374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lehmann K, Janda E, Pierreux CE, Rytomaa M, Schulze A, McMahon M et al. (2000). Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev 14: 2610–2622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin HT, Steller MA, Aish L, Hanada T, Chishti AH . (2004). Differential expression of human Dlg in cervical intraepithelial neoplasias. Gynecol Oncol 93: 422–428.

    Article  CAS  PubMed  Google Scholar 

  • Massimi P, Gammoh N, Thomas M, Banks L . (2004). HPV E6 specifically targets different cellular pools of its PDZ domain-containing tumour suppressor substrates for proteasome-mediated degradation. Oncogene 23: 8033–8039.

    Article  CAS  PubMed  Google Scholar 

  • McLachlan RW, Yap AS . (2007). Not so simple: the complexity of phosphotyrosine signaling at cadherin adhesive contacts. J Mol Med 85: 545–554.

    Article  CAS  PubMed  Google Scholar 

  • Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM et al. (2005). BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436: 720–724.

    Article  CAS  PubMed  Google Scholar 

  • Nakagawa S, Huibregtse JM . (2000). Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase. Mol Cell Biol 20: 8244–8253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakagawa S, Yano T, Nakagawa K, Takizawa S, Suzuki Y, Yasugi T et al. (2004). Analysis of the expression and localisation of a LAP protein, human scribble, in the normal and neoplastic epithelium of uterine cervix. Br J Cancer 90: 194–199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Navarro C, Nola S, Audebert S, Santoni MJ, Arsanto JP, Ginestier C et al. (2005). Junctional recruitment of mammalian Scribble relies on E-cadherin engagement. Oncogene 24: 4330–4339.

    Article  CAS  PubMed  Google Scholar 

  • Nguyen ML, Nguyen MM, Lee D, Griep AE, Lambert PF . (2003). The PDZ ligand domain of the human papillomavirus type 16 E6 protein is required for E6's induction of epithelial hyperplasia in vivo. J Virol 77: 6957–6964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Osmani N, Vitale N, Borg JP, Etienne-Manneville S . (2006). Scrib controls Cdc42 localization and activity to promote cell polarization during astrocyte migration. Curr Biol 16: 2395–2405.

    Article  CAS  PubMed  Google Scholar 

  • Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC et al. (2006). Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci USA 103: 12405–12410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL . (2005). Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307: 1603–1609.

    Article  CAS  PubMed  Google Scholar 

  • Pagliarini RA, Xu T . (2003). A genetic screen in Drosophila for metastatic behavior. Science 302: 1227–1231.

    Article  CAS  PubMed  Google Scholar 

  • Park JI, Lee MG, Cho K, Park BJ, Chae KS, Byun DS et al. (2003). Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. Oncogene 22: 4314–4332.

    Article  CAS  PubMed  Google Scholar 

  • Pegtel DM, Ellenbroek SI, Mertens AE, van der Kammen RA, de Rooij J, Collard JG . (2007). The Par-Tiam1 complex controls persistent migration by stabilizing microtubule-dependent front-rear polarity. Curr Biol 17: 1623–1634.

    Article  CAS  PubMed  Google Scholar 

  • Qin Y, Capaldo C, Gumbiner BM, Macara IG . (2005). The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J Cell Biol 171: 1061–1071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reginato MJ, Mills KR, Becker EB, Lynch DK, Bonni A, Muthuswamy SK et al. (2005). Bim regulation of lumen formation in cultured mammary epithelial acini is targeted by oncogenes. Mol Cell Biol 25: 4591–4601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarkisian CJ, Keister BA, Stairs DB, Boxer RB, Moody SE, Chodosh LA . (2007). Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nat Cell Biol 9: 493–505.

    Article  CAS  PubMed  Google Scholar 

  • Schreiber K, Cannon RE, Karrison T, Beck-Engeser G, Huo D, Tennant RW et al. (2004). Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors. Oncogene 23: 3972–3979.

    Article  CAS  PubMed  Google Scholar 

  • Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW . (1997). Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88: 593–602.

    Article  CAS  PubMed  Google Scholar 

  • Seton-Rogers SE, Brugge JS . (2004). ErbB2 and TGF-beta: a cooperative role in mammary tumor progression? Cell Cycle 3: 597–600.

    Article  CAS  PubMed  Google Scholar 

  • Seton-Rogers SE, Lu Y, Hines LM, Koundinya M, LaBaer J, Muthuswamy SK et al. (2004). Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci USA 101: 1257–1262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Settle M, Gordon MD, Nadella M, Dankort D, Muller W, Jacobs JR . (2003). Genetic identification of effectors downstream of Neu (ErbB-2) autophosphorylation sites in a Drosophila model. Oncogene 22: 1916–1926.

    Article  CAS  PubMed  Google Scholar 

  • Shin I, Kim S, Song H, Kim HR, Moon A . (2005). H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells. J Biol Chem 280: 14675–14683.

    Article  CAS  PubMed  Google Scholar 

  • Sparmann A, Bar-Sagi D . (2004). Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6: 447–458.

    Article  CAS  PubMed  Google Scholar 

  • Stanton Jr VP, Nichols DW, Laudano AP, Cooper GM . (1989). Definition of the human raf amino-terminal regulatory region by deletion mutagenesis. Mol Cell Biol 9: 639–647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Storey A, Banks L . (1993). Human papillomavirus type 16 E6 gene cooperates with EJ-ras to immortalize primary mouse cells. Oncogene 8: 919–924.

    CAS  PubMed  Google Scholar 

  • Thomas M, Massimi P, Navarro C, Borg JP, Banks L . (2005). The hScrib/Dlg apico-basal control complex is differentially targeted by HPV-16 and HPV-18 E6 proteins. Oncogene 24: 6222–6230.

    Article  CAS  PubMed  Google Scholar 

  • Woodhouse E, Hersperger E, Shearn A . (1998). Growth, metastasis, and invasiveness of Drosophila tumors caused by mutations in specific tumor suppressor genes. Dev Genes Evol 207: 542–550.

    Article  CAS  PubMed  Google Scholar 

  • Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon M . (1997). Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol 17: 5598–5611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woodworth CD, Gaiotti D, Michael E, Hansen L, Nees M . (2000). Targeted disruption of the epidermal growth factor receptor inhibits development of papillomas and carcinomas from human papillomavirus-immortalized keratinocytes. Cancer Res 60: 4397–4402.

    CAS  PubMed  Google Scholar 

  • Yin G, Haendeler J, Yan C, Berk BC . (2004). GIT1 functions as a scaffold for MEK1-extracellular signal-regulated kinase 1 and 2 activation by angiotensin II and epidermal growth factor. Mol Cell Biol 24: 875–885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Macara IG . (2006). The polarity protein PAR-3 and TIAM1 cooperate in dendritic spine morphogenesis. Nat Cell Biol 8: 227–237.

    Article  CAS  PubMed  Google Scholar 

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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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  1. L E Dow

    Present address: 3Current address: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA,

Authors and Affiliations

  1. Research Division, Cell Cycle and Cancer Genetics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    L E Dow, I A Elsum, C L King, K M Kinross & P O Humbert

  2. Research Division, Cell Cycle and Development Laboratories, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    H E Richardson

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  1. L E Dow
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Correspondence to P O Humbert.

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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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