Identification of novel TIPRL and alpha4-regulated targets of type 2A phosphatases in signaling pathways and gene expression control.

Abstract

Living cells are constantly responding to a great variety of stimuli, which are interpreted and integrated by signaling pathways and result in a biological response - for example, differenciation, apoptosis or migration. These pathways are regulated by kinases and phosphatases. Recent large scale efforts have been made to identify and characterize kinase substrates, but phosphatase substrates remain poorly characterized. Type 2A phosphatases (PP2A, PP4 and PP6) act on many substrates and regulate most cellular processes such as transcription, translation, cell cycle progression, signal transduction and apoptosis. Each one of these phosphatases have their own set of regulatory subunits, but they share alpha4/Tap42 and TIPRL/Tip41 as common regulators. These two proteins have been caractherized as important players in the yeast nutrient sensing pathway regulated by the TOR kinase, but the role of their mammalian orthologues is still unclear. This project was designed to provide a global and integrative descripion of cellular processes which are regulated by alpha4- and TIPRL-associated phosphatase pools. To this end, we propose a combined approach which employs proteomic strategies to identify their dephosphorylation targets and microarray analysis to assess their role in gene expression control.