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PP1 Inhibitor Induces Degradation of RETMEN2A and RETMEN2B Oncoproteins through Proteosomal Targeting¹

Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan [C. C., P. M., M. A. P., I. B.]; Consiglio Nazionale Ricerche Cellular and Molecular Pharmacology Center Department of Pharmacology, University of Milan, 32 Milan [C. P.]; and Istituto FIRC Oncologia Molecolare, Federazione Italiana Ricerca Cancro Institute of Molecular Oncology, 20139 Milan [M. A. P.], Italy

RET tyrosine kinase oncoproteins are potential targets for anticancer therapy. We show here that along with the inhibition of RET tyrosine phosphorylation, the pyrazolo-pyrimidine inhibitor PP1 induces RETMEN2A and RETMEN2B oncoprotein destruction. In fact, as a consequence of PP1 treatment, RET oncoproteins translocate from the outer limiting membrane to inner cellular compartments and are rapidly addressed to the degradative pathway. The cleavage of RET oncoproteins is associated with an impairment of RET mitogenic signaling pathways that causes a reversion of the oncogenic transformation and establishes a long-term cytostatic effect. By using specific inhibitors of both the proteosome and the lysosome, we assessed that PP1 targets RET oncoproteins to proteosomal, rather than lysosomal, degradation. In this context of studies, we interestingly demonstrated that RETMEN2A and RETMEN2B receptors are constitutively ubiquitinated and interact with the ubiquitin ligase c-Cbl. Moreover, PP1 does not modify these interactions, although it indeed causes RET dephosphorylation. Therefore, even if the degradative pathway stimulated by the inhibitor appears to be mediated by the proteosome, PP1 does not seem to enhance nor promote receptor ubiquitination. These observations lead us to favor two models for PP1-induced RET oncoprotein degradation: either PP1-mediated RET dephosphorylation per se targets the oncoproteins for destruction or alternatively, PP1 insertion in the RET ATP-binding pocket promotes a mechanism for fast stress-induced degradation. The use of PP1, which therefore acts as a degradation-inducing factor, may represent a promising new strategy to selectively target RET oncogenic products for destruction and holds promise for future medullary thyroid cancer therapy.

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