PHLPP phosphatases are master regulators of cellular receptor tyrosine kinase levels (802.19)

Abstract

Growth factor receptor levels are aberrantly high in diverse cancers, driving the proliferation and survival of tumor cells. Understanding the molecular basis for this aberrant elevation has profound clinical applications. Here we show that the PH domain leucine‐rich repeat protein phosphatase (PHLPP) suppresses the steady‐state levels of receptor tyrosine kinases (RTKs) by a novel mechanism unrelated to its previously described function as the hydrophobic motif phosphatase for AKT, protein kinase C and S6 kinase. Specifically, genetic depletion and pharmacological studies reveal that PHLPP1 and PHLPP2 promote histone deacetylase (HDAC)‐dependent repression of the transcription of diverse growth factor receptors, including the EGF receptor. These data uncover a novel, and much broader, role for PHLPP in regulation of growth factor signaling beyond its direct inactivation of AKT: by suppressing RTK levels, PHLPP dampens the downstream signaling output of two major oncogenic pathways, the PI3 kinase/AKT and the RAS/ERK pathways. Our data are consistent with a model in which PHLPP is a master regulator of the RTK signaling output of cells.