CPI-17 drives oncogenic Ras signaling in human melanomas via Ezrin-Radixin-Moesin family proteins

// Lars Björn Riecken 1 , Ansgar Zoch 1 , Ulrike Wiehl 1 , Sabine Reichert 1,2 , Ingmar Scholl 1 , Yan Cui 1 , Mirjana Ziemer 3 , Ulf Anderegg 3 , Christian Hagel 4 and Helen Morrison 1 1 Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany 2 Department of Cell and Developmental Biology, University College London, London, United Kingdom 3 Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie, Universität Leipzig, Leipzig, Germany 4 Department of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Correspondence to: Helen Morrison, email: // Keywords : CPI-17, ERM, Ras, cancer, melanoma Received : January 14, 2016 Accepted : October 21, 2016 Published : October 26, 2016 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.