Molecular Basis of Competition between HSF2 and Catalytic Subunit for Binding to the PR65/A Subunit of PP2A

Hong, Yan; Lubert, Eric J.; Rodgers, David W.; Sarge, Kevin D.

doi:10.1006/bbrc.2000.2733

Cited by 17 publications

(17 citation statements)

References 26 publications

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“…Our results indicate that the tetratricopeptide repeat region of PP5 is sufficient for this interaction. We also found that the sequence surrounding the loop region of HEAT repeat 11 within the A subunit, which was previously shown to be important for binding to PP2Ac and HSF2, is also important for interaction with PP5 (18,19). Furthermore, we found that PP5 associates with B subunits in vivo, indicating that PP5 exists in a heterotrimeric form reminiscent of the PP2A enzyme.…”

supporting

confidence: 69%

“…PP5 also interacts with heat shock protein 90 in complexes with glucocorticoid receptors, and it has been demonstrated that overexpression of the TPR domain of PP5 blocks glucocorticoid-induced gene transcription (15,16). Thus, PP5 has distinctive biochemical and biological properties because of its N-terminal TPR domain.We have been characterizing an interaction between the A subunit of PP2A and a member of the heat shock transcription factor family, heat shock factor 2 (HSF2) (17,18). Our data suggests that HSF2 competes with PP2Ac by binding to the same region of the A subunit and that HSF2 may represent a new type of PP2A regulatory protein.…”

mentioning

confidence: 95%

“…We have been characterizing an interaction between the A subunit of PP2A and a member of the heat shock transcription factor family, heat shock factor 2 (HSF2) (17,18). Our data suggests that HSF2 competes with PP2Ac by binding to the same region of the A subunit and that HSF2 may represent a new type of PP2A regulatory protein.…”

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confidence: 95%

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Interaction between Protein Phosphatase 5 and the A subunit of Protein Phosphatase 2A

Lubert¹,

Hong²,

Sarge³

2001

Journal of Biological Chemistry

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Members of the phosphoprotein phosphatase family of serine/threonine phosphatases are thought to exist in different native oligomeric complexes. Protein phosphatase 2A (PP2A) is composed of a catalytic subunit (PP2Ac) that complexes with an A subunit, which in turn also interacts with one of many B subunits that regulate substrate specificity and/or (sub)cellular localization of the enzyme. Another family member, protein phosphatase 5 (PP5), contains a tetratricopeptide repeat domain at its N terminus, which has been suggested to mediate interactions with other proteins. PP5 was not thought to interact with partners homologous to the A or B subunits that exist within PP2A. However, our results indicate that this may not be the case. A yeast two-hybrid screen revealed an interaction between PP5 and the A subunit of PP2A. This interaction was confirmed for endogenous proteins in vivo using immunoprecipitation analysis and for recombinant proteins by in vitro binding experiments. Our results also indicate that the tetratricopeptide repeat domain of PP5 is required and sufficient for this interaction. In addition, immunoprecipitated PP5 contains associated B subunits. Thus, our results suggest that PP5 can exist in a PP2A-like heterotrimeric form containing both A and B subunits.The reversible phosphorylation of proteins, catalyzed by protein kinases and phosphatases, is a major mechanism for regulating many cellular processes, including intermediary metabolism, cell cycle progression, DNA replication, transcription, and protein translation (1-3). It is estimated that one-third of all cellular proteins undergo reversible phosphorylation, which cells utilize to regulate the functional properties of key regulatory proteins involved in specific pathways (4).Based on homology of amino acid sequences and the similarity of three-dimensional structures, phosphoprotein phosphatases (PPPs) 1 are divided into three families designated PPP, PPM, and PTP (5, 6). The PPP and PPM families are comprised of phosphoserine-and phosphothreonine-specific enzymes, whereas the PTP family is comprised of phosphotyrosine-specific and/or dual specificity phosphatases. As suggested by the name, dual specificity phosphatases can dephosphorylate all three phosphoresidues (7). Protein phosphatase 2A (PP2A) together with PP1, PP2B (calcineurin), PP4, PP5, PP6, and PP7 are classified in the PPP family (4). PP2A exists as a heterotrimer composed of a catalytic subunit (PP2Ac), an A subunit (also known as PR65), and a B subunit. There are three major families of B subunits, PR55/B, PR61/BЈ, PR72/BЉ, with multiple isoforms within each family (4 -6, 8). The association of PP2Ac with different B subunits modulates the activity, substrate specificity, and/or (sub)cellular location of the holoenzymes, enabling them to control numerous cellular functions (3, 4, 9, 10).Protein phosphatase 5 (PP5), another member of the PPP family of phosphatases, differs from the other serine/threonine phosphatases in that it contains regulatory and (sub)cellular targetin...

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confidence: 69%

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confidence: 95%

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Interaction between Protein Phosphatase 5 and the A subunit of Protein Phosphatase 2A

Lubert¹,

Hong²,

Sarge³

2001

Journal of Biological Chemistry

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“…PP2A also associates with numerous cellular proteins that are involved in growth regulation Virshup, 2000). They include several protein kinases (Abraham et al, 2000;Heriche et al, 1997;Lebrin et al, 1999;Westphal et al, 1998Westphal et al, , 1999, the Rb-related protein p107 (Voorhoeve et al, 1999), heat shock protein HSF2 (Hong et al, 2000), adenomatous polyposis coli (APC) protein (Seeling et al, 1999), axin (Hsu et al, 1999), translation termination factor eRF1 (Andjelkovic et al, 1996), HOX 11 (Kawabe et al, 1997), myeloid leukemia-associated protein SET (Li et al, 1996), caspase 3 (Santoro et al, 1998), and Bc12 (Deng et al, 1998).…”

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confidence: 99%

Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the Aβ subunit gene

2001

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Protein phosphatase 2A (PP2A) consists of three subunits, A, B and C. The A and B subunits have regulatory functions while C is the catalytic subunit. PP2A core enzyme is composed of subunits A and C, and the holoenzyme of subunits A, B and C. All subunits exist as multiple isoforms or splice variants. The A subunit exists as two isoforms, Aa and Ab. Here we report about the properties of eight Ab mutants, which were found in human lung and colon cancer. These mutants were reconstructed by site-directed mutagenesis and assayed for their ability to bind B and C subunits. Two mutants showed decreased binding of PR72, a member of the B'' family of B subunits, but normal C subunit binding; two mutants exhibited decreased binding of the C subunit and of B''/PR72; and one mutant showed increased binding of both the C subunit and B''/PR72. Of three mutants that behaved like the wildtype Ab subunit, one is a polymorphic variant and another one is altered outside the binding region for B and C subunits. Importantly, we also found that the wildtype Aa and Ab isoforms, although 85% identical, are remarkably di erent in their ability to bind B and C subunits. Our ®ndings may have important implications in regard to the role of PP2A as a tumor suppressor.

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“…Inhibitory factors are known to attenuate PP2A catalytic activity by competing with the regulatory subunit for association with the PP2A trimer. This replacement of the regulatory subunit with other proteins can result in the partial or total loss of PP2A catalytic activity (15,16,44). This loss or misregulation of PP2A activity results in a variety of defects, such as increased cellular transformation (44) and abnormal chromosomal segregation (25).…”

mentioning

confidence: 99%

Protein Phosphatase 2A Activity Affects Histone H3 Phosphorylation and Transcription in Drosophila melanogaster

Nowak

Pai

Corcés

2003

Molecular and Cellular Biology

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Transcriptional activation of the heat shock genes during the heat shock response in Drosophila has been intimately linked to phosphorylation of histone H3 at serine 10, whereas repression of non-heat-shock genes correlates with dephosphorylation of histone H3. It is then possible that specific kinase and/or phosphatase activities may regulate histone phosphorylation and therefore transcription activation and repression, respectively. We find that treatment of cells with strong phosphatase inhibitors interferes with the genome-wide dephosphorylation of histone H3 normally observed at non-heat-shock genes during heat shock. Mutants in protein phosphatase type 2A (PP2A) also display reduced genome-wide H3 dephosphorylation, and sites of H3 phosphorylation that do not contain heat shock genes remain transcriptionally active during heat shock in PP2A mutants. Finally, the SET protein, a potent and highly selective inhibitor of PP2A activity that inhibits PP2A-mediated dephosphorylation of Ser10-phosphorylated H3, is detected at transcriptionally active regions of polytene chromosomes. These results suggest that activation and repression of gene expression during heat shock might be regulated by changes in PP2A activity controlled by the SET protein.

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Molecular Basis of Competition between HSF2 and Catalytic Subunit for Binding to the PR65/A Subunit of PP2A

Cited by 17 publications

References 26 publications

Interaction between Protein Phosphatase 5 and the A subunit of Protein Phosphatase 2A

Interaction between Protein Phosphatase 5 and the A subunit of Protein Phosphatase 2A

Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the Aβ subunit gene

Protein Phosphatase 2A Activity Affects Histone H3 Phosphorylation and Transcription in Drosophila melanogaster

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