Deregulated PP1alpha phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism

Abstract

The mitogen-activated protein kinase (MAPK) pathway is frequently aberrantly activated in advanced cancers, including metastatic prostate cancer (CaP). However, activating mutations or gene rearrangements among MAPK signaling components, such as Ras and Raf, are not always observed in cancers with hyperactivated MAPK. The mechanisms underlying MAPK activation in these cancers remain largely elusive. Here we discover that genomic amplification of the PPP1CA gene is highly enriched in metastatic human CaP. We further identify an S6K/PP1alpha/B-Raf signaling pathway leading to activation of MAPK signaling that is antagonized by the PML tumor suppressor. Mechanistically, we find that PP1alpha acts as a B-Raf activating phosphatase and that PML suppresses MAPK activation by sequestering PP1alpha into PML nuclear bodies, hence repressing S6K-dependent PP1alpha phosphorylation, 14-3-3 binding and cytoplasmic accumulation. Our findings therefore reveal a PP1alpha/PML molecular network that is genetically altered in human cancer towards aberrant MAPK activation, with important therapeutic implications.