PROTEIN PHOSPHATASE 2A IN CELLULAR SIGNALING
Principal Investigator: M Mumby
Abstract: Protein phosphatase 2A (PP2A) is a major form of serine/threonine phosphatase in many cell types. The purified enzyme is a heterotrimer composed of a catalytic subunit (C) and two regulatory subunits (A and B). While the A and C subunits appear to be relatively homogeneous, there are multiple distinct families of regulatory proteins (generally classified as B subunits) that create a diversity of enzyme forms with distinct enzymatic activities and substrate specificities. Biochemical and genetic evidence have shown that PP2A is involved in a number of cellular signalling pathways, including those controlling cell growth and proliferation. Alteration of PP2A activity by protein-protein interaction plays an important role in modulating signalling through these pathways. For example, interaction of polyomavirus middle tumor antigen with the AC complex is necessary but not sufficient for transformation by this protein. Our goal is to determine the molecular basis for the interaction of regulatory proteins with PP2A, the effects of these interactions on enzyme activity and specificity, and how these interactions control the phosphorylation states of cellular proteins. The A subunit plays a central role in bringing together the catalytic subunit with an array of regulatory proteins (B subunits and tumor antigens). We plan to determine the molecular basis for the interaction of the A subunit with the catalytic subunit and with previously characterized regulatory subunits. The binding domains and relevant amino acids involved in these interactions will be identified by biochemical methods, by deletional and site-directed mutagenesis of the cloned cDNA, and by structural analysis of the A subunit using circular dichroism and X-ray crystallography. New proteins that interact with and regulate the activity of PP2A will be identified by the polymerase chain reaction and cDNA cloning, by functional analysis, and by A subunit affinity chromatography. The molecular basis for the regulation of the activity and specificity of PP2A will be determined by identifying how previously characterized and newly identified regulatory proteins interact with the catalytic subunit in the heterotrimeric complexes. C subunit domains required for interaction with the A subunit will be identified by chemical crosslinking and deletional and site-directed mutagenesis.
Funding Period: 1983-07-01 - 2003-03-31
more information: NIH RePORT
- PP2A: unveiling a reluctant tumor suppressorMarc Mumby
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Cell 130:21-4. 2007..Recent findings, including work in this issue by Junttila et al. (2007), provide convincing evidence that suppression of PP2A activity cooperates with other oncogenic changes to cause transformation of multiple cell types...