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

Lars Björn Riecken,Mirjana Ziemer,Ingmar Scholl,Yan Cui,Helen Morrison,Ansgar Zoch,Christian Hagel,Ulrike Wiehl,Sabine Reichert,Ulf Anderegg

doi:10.18632/oncotarget.12919

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.

Highlights

The small GTPase Ras is a central signaling component that translates a multitude of extracellular stimuli into well-defined cellular processes - including proliferation, migration and differentiation [1]
Loss of MYPT1 expression consistently yielded a strong increase in ezrin phosphorylation, correlating noticeably with the efficiency of MYTP1 depletion (Figure 1C).MYPT1-dependent ezrin dephosphorylation was validated by downregulation of MYPT1 expression in NIH3T3 mouse fibroblasts (Figure 1D), using a lentiviral short-hairpin RNA (shRNA) approach
This study identified ERM proteins as downstream targets of a regulatory CPI-17-MYPT1-PP1δ switch controlling ERM phosphorylation and activation (Figure 1, Figure 3A, Figure 6)

Summary

Introduction

The small GTPase Ras is a central signaling component that translates a multitude of extracellular stimuli into well-defined cellular processes - including proliferation, migration and differentiation [1]. Tumor cells exhibiting hyperactive Ras signaling are independent from extracellular mitogenic input, showing uncontrolled cellular growth and proliferation [1, 3]. We have reported that C-kinase potentiated protein phosphatase-1 inhibitor of 17 kDa (CPI-17) can drive Ras activity and promote tumorigenic transformation by inhibiting the tumor suppressor Merlin [6]. CPI-17 directly controls Merlin activity by regulating its phosphorylation status via the myosin phosphatase MYPT1-PP1δ. Merlin and the ERM proteins are regulated in an opposing manner, i.e. C-terminal phosphorylation inactivates Merlin but activates ERM proteins [7, 8]. We show that ERM proteins, like Merlin, are regulated by a CPI17 - MYPT1-PP1δ switch, which results in hyperactive Ras signaling and tumorigenic growth.

Methods

Results

Conclusion