Characterization of the type 2A phosphatase regulatory protein, TIPRL and alpha4 / Caracterização das proteinas TIPRL e alfa4, reguladores de fosfatases 2A

AUTOR(ES)
DATA DE PUBLICAÇÃO

2009

RESUMO

Cells respond constantly to a variety of stimuli, which are interpreted and integrated through signaling networks, giving rise to biological responses. Defects in this circuitry are a cause of many diseases, including cancer. Protein phosphatases are enzymes which remove phosphate groups from kinase substrates, relying mainly on regulatory subunits for their substrate specificity. Type 2A phosphatases belong to the PPP subfamily, which is formed by PP2A, PP4 and PP6. PP2A is the major soluble serine/threonine phosphatase in animal cells and is found predominantly as a heterotrimer composed of a catalytic (C), a regulatory (B, B , B or B ) and a scaffold (PR65/A) subunit. Type 2A phosphatases play a major role in the yeast TOR signaling pathway through their interaction with the essential protein Tap42. Tip41 was identified as a Tap42 interacting protein and regulator of the TOR pathway. a4, the mammalian orthologue of Tap42, regulates many cellular processes such as differentiation, development, cell migration and apoptosis as a conserved type 2A phosphatase regulator. TIPRL, the mammalian orthologue of Tip41, is still poorly characterized. The objective of the present work was to analyse the function of a4 and TIPRL and improve the understanding of their role as type 2A phosphatase regulators. The structural characterization of a4 using SAXS analyses, circular dichroism and limited proteolysis, showed that these proteins are formed by an a-helical N-terminal domain and an unfolded C-terminal domain. A screen for TIPRL interacting proteins identified PP2Ac, PP4c and PP6c and also the transcription factors MafB and TAF10. Unlike their yeast conterparts, a4 and TIPRL do not interact directly, but rather form a ternary complex with PP2A. A search for type 2A phosphatase substrates regulated by TIPRL identified the splicing factor SF2/ASF and its regulatory protein SF2p32. Our results suggest a structural model for the regulation of type 2A phosphatases by a4 and show that TIPRL is a novel common regulator of these phosphatases which functions in regulation of gene expression

ASSUNTO(S)

proteina tap42 tap42 protein yeast two-hybrid protein phosphatase 2a proteina fosfatase 2a proteins tip41 protein duplo-hibrido de levedura proteinas - análise proteina tip41

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