title: CPI-17 drives oncogenic Ras signaling in human melanomas via Ezrin-Radixin-Moesin family proteins.
abstract: Hyperactive Ras signaling has strong oncogenic effects causing several different forms of cancer. Hyperactivity is frequently induced by mutations within Ras itself, which account for up to 30% of all human cancers. In addition, hyperactive Ras signaling can also be triggered independent of Ras by either mutation or by misexpression of various upstream regulators and immediate downstream effectors. We have previously reported that C-kinase potentiated protein phosphatase-1 inhibitor of 17 kDa (CPI-17) can drive Ras activity and promote tumorigenic transformation by inhibition of the tumor suppressor Merlin. We now describe an additional element of this oncogenic mechanism in the form of the ezrin-radixin-moesin (ERM) protein family, which exhibits opposing roles in Ras activity control. Thus, CPI-17 drives Ras activity and tumorigenesis in a two-fold way; inactivation of the tumor suppressor merlin and activation of the growth promoting ERM family. The in vivo significance of this oncogenic switch is highlighted by demonstrating CPI-17's involvement in human melanoma pathogenesis.
authors: Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany.
authors: Lars Björn
authors: LB
authors: Riecken
authors: Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany.
authors: Ansgar
authors: A
authors: Zoch
authors: Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany.
authors: Ulrike
authors: U
authors: Wiehl
authors: Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany.|Department of Cell and Developmental Biology, University College London, London, United Kingdom.
authors: Sabine
authors: S
authors: Reichert
authors: Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany.
authors: Ingmar
authors: I
authors: Scholl
authors: Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany.
authors: Yan
authors: Y
authors: Cui
authors: Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universität Leipzig, Leipzig, Germany.
authors: Mirjana
authors: M
authors: Ziemer
authors: Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universität Leipzig, Leipzig, Germany.
authors: Ulf
authors: U
authors: Anderegg
authors: Department of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Christian
authors: C
authors: Hagel
authors: Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany.
authors: Helen
authors: H
authors: Morrison
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins; D043263:Myosin-Light-Chain Phosphatase / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D043263:Myosin-Light-Chain Phosphatase; D025581:Neurofibromin 2; D010749:Phosphoprotein Phosphatases; D018631:ras Proteins; D000099149:Ezrin; C107507:PPP1R14A protein, human; C071058:moesin; C071776:radixin; C490372:PPP1R12A protein, human
keywords: CPI-17; ERM; Ras; cancer; melanoma