Specific interactions of PP2A and PP2A-like phosphatases with the yeast PTPA homologues, Ypa1 and Ypa2

Hoof, Christine Van; Martens, Ellen; Longin, Sari; Jordens, Jan; Stevens, Ilse; Janssens, Veerle; Goris, Jozef

doi:10.1042/bj20040887

Cited by 43 publications

(62 citation statements)

References 31 publications

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“…This insertion appears feasible from a structural perspective and could possibly be involved in changing the protein-protein interaction pattern of PTPA. The yeast PTPA homologs Rrd1 and Rrd2 interact with the conserved Tap42 protein (␣4 in humans) and with the type 2A phosphatases (16,17). Tap42 also interacts with type 2A phosphatases, and this complex is a crucial part in mediating the signal through the TOR pathway, a nutrient-responsive signaling pathway (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

“…PTPA is an essential protein as revealed by its high evolutionary conservation as well as the lethality of the deletion of the two PTPA homologs in yeast, Rrd1 and Rrd2, in certain nutritional backgrounds (15). Rrd1/2 also interact with other less abundant type 2A phosphatases (16,17). Interestingly, the effect of deleting Rrd1/2 is more severe than deletion of the yeast PP2Ac, most likely due to the fact that the different type 2A phosphatases in yeast can partly take over each others roles (18).…”

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confidence: 99%

“…Interestingly, the effect of deleting Rrd1/2 is more severe than deletion of the yeast PP2Ac, most likely due to the fact that the different type 2A phosphatases in yeast can partly take over each others roles (18). However, they all interact with the PTPA subunits (16), an interaction that appears to be critical for the 2A phosphatase activity in the cell.…”

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confidence: 99%

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The Crystal Structure of a Human PP2A Phosphatase Activator Reveals a Novel Fold and Highly Conserved Cleft Implicated in Protein-Protein Interactions

Magnusdottir

Stenmark

Flodin

et al. 2006

Journal of Biological Chemistry

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Protein phosphatase 2A (PP2A) is a heterotrimeric Ser/Thr phosphatase that is involved in regulating a plethora of signaling pathways in the cell, making its regulation a critical part of the well being of the cell. For example, three of the non-catalytic PP2A subunits have been linked to carcinogenic events. Therefore, the molecular basis for the complicated protein-protein interaction pattern of PP2A and its regulators is of special interest. The PP2A phosphatase activator (PTPA) protein is highly conserved from humans to yeast. It is an activator of PP2A and has been shown to be essential for a fully functional PP2A, but its mechanism of activation is still not well defined. We have solved the crystal structure of human PTPA to 1.6 Å . It reveals a twodomain protein with a novel fold comprised of 13 ␣-helices. We have identified a highly conserved cleft as a potential region for interaction with peptide segments of other proteins. Binding studies with ATP and its analogs are not consistent with ATP being a cofactor/substrate for PTPA as had previously been proposed. The structure of PTPA can serve as a basis for structurefunction studies directed at elucidating its mechanism as an activator of PP2A.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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The Crystal Structure of a Human PP2A Phosphatase Activator Reveals a Novel Fold and Highly Conserved Cleft Implicated in Protein-Protein Interactions

Magnusdottir

Stenmark

Flodin

et al. 2006

Journal of Biological Chemistry

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“…Rrd2p binds directly to the PP2A catalytic subunits Pph21p and Pph22p, and is more potent in the activation of PP2A catalytic subunits than Rrd1p. It has also been suggested that Rrd1p and Rrd2p may cooperate in the activation of PP2A (Van Hoof et al 2005). Rrd1p also activates the PP2A-related phosphatase Sit4p (Douville et al 2004;Mitchell and Sprague 2001).…”

Section: S Pombe Ptpa Genesmentioning

confidence: 99%

Characterization of ypa1 and ypa2, the Schizosaccharomyces pombe Orthologs of the Peptidyl Proyl Isomerases That Activate PP2A, Reveals a Role for Ypa2p in the Regulation of Cytokinesis

Goyal

2012

Genetics

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The Schizosaccharomyces pombe septation initiation network (SIN) regulates cytokinesis. Cdc7p is the first kinase in the core SIN; we have screened genetically for SIN regulators by isolating cold-sensitive suppressors of cdc7-24. Our screen yielded a mutant in SPAC1782.05, one of the two fission yeast orthologs of mammalian phosphotyrosyl phosphatase activator. We have characterized this gene and its ortholog SPAC4F10.04, which we have named ypa2 and ypa1, respectively. We find that Ypa2p is the major form of protein phosphatase type 2A activator in S. pombe. A double ypa1-D ypa2-D null mutant is inviable, indicating that the two gene products have at least one essential overlapping function. Individually, the ypa1 and ypa2 genes are essential for survival only at low temperatures. The ypa2-D mutant divides at a reduced cell size and displays aberrant cell morphology and cytokinesis. Genetic analysis implicates Ypa2p as an inhibitor of the septation initiation network. We also isolated a cold-sensitive allele of ppa2, the major protein phosphatase type 2A catalytic subunit, implicating this enzyme as a regulator of the septation initiation network. SCHIZOSACCHAROMYCES pombe cells take the form of a cylinder capped by hemispherical ends. During interphase, cells grow mainly at their tips. Cell elongation ceases after mitotic commitment, and the cytoskeleton is reorganized in preparation for nuclear and cell division (reviewed by McCully and Robinow 1971;Mitchison and Nurse 1985;Marks et al. 1986;Hagan and Hyams 1988;Hagan 1998). The cell divides by fission after forming a septum in the middle of the cell. The site of division is defined at the onset of mitosis (Daga and Chang 2005), by the formation of an actomyosin contractile ring (CAR), whose assembly continues throughout mitosis (Wu et al. 2003;Pollard 2008;Pollard and Wu 2010). At the end of anaphase, the CAR is thought to guide synthesis of the multilayered division septum (reviewed by (Ishiguro 1998;Sipiczki 2007). Septation Initiation NetworkThe S. pombe septation initiation network (SIN) is a network of protein kinases that is essential for cytokinesis in the mitotic cycle; reviewed by (Gould and Simanis 1997;Simanis 2003;Wolfe and Gould 2005;Goyal et al. 2011). It is tightly regulated through the mitotic cell cycle to assure proper coordination of mitosis and cytokinesis, and during meiosis, where it is essential for spore formation (Krapp et al. 2006). Signaling requires the activity of three protein kinases, each of which has a regulatory subunit (kinase regulator); Cdc7p-Spg1p (Fankhauser and Simanis 1994;Schmidt et al. 1997;Mehta and Gould 2006), Sid1p-Cdc14p (Fankhauser and Simanis 1993;Guertin et al. 2000;Guertin and McCollum 2001), and Sid2p-Mob1p (Sparks et al. 1999;Hou et al. 2000;Salimova et al. 2000). SIN signaling is modulated by the nucleotide status of the GTPase Spg1p (Schmidt et al. 1997;Sohrmann et al. 1998), which is determined by the balance of spontaneous nucleotide exchange, a putative GEF, Etd1p Garcia-Cortes and McCollu...

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“…TIP41 dephosphorylation correlates with an increased association of TIP41 with TAP42, but here too, the physiological relevance of TIP41 phosphorylation in this process has not been confirmed (Jacinto et al, 2001). Presumably, the phosphorylation status of TAP42 and/or its association with TIP41 alters the substrate specificity of associated phosphatases (Du¨vel et al, 2003;Du¨vel and Broach, 2004;Van Hoof et al, 2005;Zheng and Jiang, 2005). The latest model (Yan et al, 2006) posits that TORC1 regulates TAP42-associated phosphatases via direct physical interaction, which sequesters the phosphatases with TORC1 at membranes.…”

Section: Torc1 Regulated Protein Phosphatasesmentioning

confidence: 99%

Cell growth control: little eukaryotes make big contributions

2006

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The story of rapamycin is a pharmaceutical fairytale. Discovered as an antifungal activity in a soil sample collected on Easter Island, this macrocyclic lactone and its derivatives are now billion dollar drugs, used in, and being evaluated for, a number of clinical applications. Taking advantage of its antifungal property, the molecular Target Of Rapamycin, TOR, was first described in the budding yeast Saccharomyces cerevisiae. TORs encode large, Ser/Thr protein kinases that reside in two distinct, structurally and functionally conserved, multi-protein complexes. In yeast, these complexes coordinate many different aspects of cell growth. TOR complex 1, TORC1, promotes protein synthesis and other anabolic processes, while inhibiting macroautophagy and other catabolic and stress-response processes. TORC2 primarily regulates cell polarity, although additional readouts of this complex are beginning to be characterized. TORC1 appears to be activated by nutrient cues and inhibited by stresses and rapamycin; however, detailed mechanisms are not known. In contrast, TORC2 is insensitive to rapamycin and physiological regulators of this complex have yet to be defined. Given the unsurpassed resources available to yeast researchers, this simple eukaryote continues to contribute to our understanding of eukaryotic cell growth in general and TOR function in particular

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Specific interactions of PP2A and PP2A-like phosphatases with the yeast PTPA homologues, Ypa1 and Ypa2

Cited by 43 publications

References 31 publications

The Crystal Structure of a Human PP2A Phosphatase Activator Reveals a Novel Fold and Highly Conserved Cleft Implicated in Protein-Protein Interactions

The Crystal Structure of a Human PP2A Phosphatase Activator Reveals a Novel Fold and Highly Conserved Cleft Implicated in Protein-Protein Interactions

Characterization of ypa1 and ypa2, the Schizosaccharomyces pombe Orthologs of the Peptidyl Proyl Isomerases That Activate PP2A, Reveals a Role for Ypa2p in the Regulation of Cytokinesis

Cell growth control: little eukaryotes make big contributions

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