1. Leibniz Institute of Age Research–Fritz-Lipmann-Institute, Beutenbergstrasse 11, 07745 Jena, Germany
2. Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, PO Box 3640, 76021 Karlsruhe, Germany
3. †Present address: Cancer Center, Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China

Correspondence to: Helen Morrison^1,2 Correspondence and requests for materials should be addressed to H.M. (Email: helen@fli-leibniz.de).

Abstract

The tumour suppressor protein merlin (encoded by the neurofibromatosis type 2 gene NF2) is an important regulator of proliferation in many cell and tissue types^{1, 2, 3, 4}. Merlin is activated by dephosphorylation at serine 518 (S518), which occurs on serum withdrawal or on cell–cell or cell–matrix contact^{5, 6}. However, the relevant phosphatase that activates merlin's tumour suppressor function is unknown. Here we identify this enzyme as the myosin phosphatase (MYPT-1–PP1). The cellular MYPT-1–PP1-specific inhibitor CPI-17 causes a loss of merlin function characterized by merlin phosphorylation, Ras activation and transformation. Constitutively active merlin (S518A) reverses CPI-17-induced transformation, showing that merlin is the decisive substrate of MYPT-1–PP1 in tumour suppression. In addition we show that CPI-17 levels are raised in several human tumour cell lines and that the downregulation of CPI-17 induces merlin dephosphorylation, inhibits Ras activation and abolishes the transformed phenotype. MYPT-1–PP1 and its substrate merlin are part of a previously undescribed tumour suppressor cascade that can be hindered in two ways, by mutation of the NF2 gene and by upregulation of the oncoprotein CPI-17.

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