Determinants for Substrate Specificity of Protein Phosphatase 2A

Slupe, Andrew M.; Merrill, Ronald A.; Strack, Stefan

doi:10.4061/2011/398751

Cited by 82 publications

(82 citation statements)

References 71 publications

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“…The most diverse regulatory B subunit gene family in both flowering plants and mammals is the B56 gene family (for review, see Farkas et al, 2007;Slupe et al, 2011), whose members exhibit a highly conserved central domain (the B56 domain; Supplemental Fig. S1) with small, variable N-and C-terminal regions (Xu et al, 2006;Cho and Xu, 2007;Magnusdottir et al, 2009).…”

Section: Plant Pp2a Subunit Gene Families Expanded Primarily Within Tmentioning

confidence: 99%

“…The canonical role of regulatory B subunits in the PP2A holoenzyme is to recognize distinct substrates for dephosphorylation (for review, see Slupe et al, 2011). Unlike the A and C subunits, the B subunit is encoded by a small number of phylogenetically unrelated, structurally distinct gene families.…”

mentioning

confidence: 99%

“…B subunit gene families have expanded, yielding multiple isoforms in both vertebrates and flowering plants. In mammals, B55 isoforms are encoded by four genes, B56 isoforms by five genes, and B72 isoforms by three genes (for review, see Slupe et al, 2011). In Arabidopsis, the B55 family is represented by two genes, the B56 family by nine genes, and the B72 family by six genes (Table I; Farkas et al, 2007).…”

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confidence: 99%

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Atypical Protein Phosphatase 2A Gene Families Do Not Expand via Paleopolyploidization

Booker

DeLong

2016

Plant Physiol.

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Protein phosphatase 2A (PP2A) presents unique opportunities for analyzing molecular mechanisms of functional divergence between gene family members. The canonical PP2A holoenzyme regulates multiple eukaryotic signaling pathways by dephosphorylating target proteins and contains a catalytic (C) subunit, a structural/scaffolding (A) subunit, and a regulatory (B) subunit. Genes encoding PP2A subunits have expanded into multigene families in both flowering plants and mammals, and the extent to which different isoform functions may overlap is not clearly understood. To gain insight into the diversification of PP2A subunits, we used phylogenetic analyses to reconstruct the evolutionary histories of PP2A gene families in Arabidopsis (Arabidopsis thaliana). Genes encoding PP2A subunits in mammals represent ancient lineages that expanded early in vertebrate evolution, while flowering plant PP2A subunit lineages evolved much more recently. Despite this temporal difference, our data indicate that the expansion of PP2A subunit gene families in both flowering plants and animals was driven by whole-genome duplications followed by nonrandom gene loss. Selection analysis suggests that the expansion of one B subunit gene family (B56/PPP2R5) was driven by functional diversification rather than by the maintenance of gene dosage. We also observed reduced expansion rates in three distinct B subunit subclades. One of these subclades plays a highly conserved role in cell division, while the distribution of a second subclade suggests a specialized function in supporting beneficial microbial associations. Thus, while whole-genome duplications have driven the expansion and diversification of most PP2A gene families, members of functionally specialized subclades quickly revert to singleton status after duplication events.

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Section: Plant Pp2a Subunit Gene Families Expanded Primarily Within Tmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Atypical Protein Phosphatase 2A Gene Families Do Not Expand via Paleopolyploidization

Booker

DeLong

2016

Plant Physiol.

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“…For example, in mammals, PP2Ac associates with a scaffolding A-a or -b subunit and an additional regulatory B subunit to form the holoenzyme and gain its full activity, PP4c binds to four unique direct binding partners and other partners, and PP6c binds to the SAPS domain proteins and other binding partners, such as ankyrin repeat-containing proteins, to form PP6 holoenzyme and build up the activity specificity (Luke et al, 1996;G.I. Chen et al, 2008;Slupe et al, 2011). However, the in vivo holoenzyme composition and developmental roles of these phosphatases are still poorly understood in plants.…”

mentioning

confidence: 99%

A PP6-Type Phosphatase Holoenzyme Directly Regulates PIN Phosphorylation and Auxin Efflux in Arabidopsis

et al. 2012

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The directional transport of the phytohormone auxin depends on the phosphorylation status and polar localization of PIN-FORMED (PIN) auxin efflux proteins. While PINIOD (PID) kinase is directly involved in the phosphorylation of PIN proteins, the phosphatase holoenzyme complexes that dephosphorylate PIN proteins remain elusive. Here, we demonstrate that mutations simultaneously disrupting the function of Arabidopsis thaliana FyPP1 (for Phytochrome-associated serine/threonine protein phosphatase1) and FyPP3, two homologous genes encoding the catalytic subunits of protein phosphatase6 (PP6), cause elevated accumulation of phosphorylated PIN proteins, correlating with a basal-to-apical shift in subcellular PIN localization. The changes in PIN polarity result in increased root basipetal auxin transport and severe defects, including shorter roots, fewer lateral roots, defective columella cells, root meristem collapse, abnormal cotyledons (small, cup-shaped, or fused cotyledons), and altered leaf venation. Our molecular, biochemical, and genetic data support the notion that FyPP1/3, SAL (for SAPS DOMAIN-LIKE), and PP2AA proteins (RCN1 [for ROOTS CURL IN NAPHTHYLPHTHALAMIC ACID1] or PP2AA1, PP2AA2, and PP2AA3) physically interact to form a novel PP6-type heterotrimeric holoenzyme complex. We also show that FyPP1/3, SAL, and PP2AA interact with a subset of PIN proteins and that for SAL the strength of the interaction depends on the PIN phosphorylation status. Thus, an Arabidopsis PP6-type phosphatase holoenzyme acts antagonistically with PID to direct auxin transport polarity and plant development by directly regulating PIN phosphorylation. INTRODUCTIONAuxin is a fundamental plant hormone that regulates almost every aspect of plant growth and development, including embryogenesis, organogenesis, apical dominance, tissue regeneration, and tropisms (reviewed in Bennett and Scheres, 2010;Grunewald and Friml, 2010;Peris et al., 2010). Auxin is transported from its sites of biosynthesis to its sites of action by a polarized auxin transport system. Molecular genetic studies in Arabidopsis thaliana have lead to the identification and functional characterization of several key players of the polarized auxin transport system, such as the auxin uptake carriers AUXIN RESISTANT1/LIKE AUX1 (AUX1/ LAX) (Swarup et al., 2008), the auxin efflux carriers, including PIN-FORMED (PIN) family proteins Chen et al., 1998;Müller et al., 1998;Friml et al., 2002;Petrásek et al., 2006), and P-glycoprotein auxin transporters ABCB1 (for ATP BINDING CASSETTE PROTEIN SUBFAMILY B1), ABCB4, and ABCB19 (Terasaka et al., 2005;Bouchard et al., 2006;Blakeslee et al., 2007;Lin and Wang, 2005). PIN proteins are asymmetrically targeted to the plant cell plasma membranes, resulting in distinct polar subcellular localization in a given tissue. For example, PIN1 is localized in the basal (rootward, lower) plasma membrane of stele cells and xylem cells in the vascular system, which is required for long-distance auxin flow from the shoot apex to the root tip Friml e...

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“…Protein phosphatase 2, regulatory subunit A, α (PPP2R1A) and β (PPP2R1B) are paralogous subunits of the heterotrimeric protein phosphatase 2 (PP2A) holoenzyme, which catalyzes the dephosphorylation of target substrate proteins (www.ensembl.org) (1). PPP2R1A and PPP2R1B belong to the Huntington-elongation-A subunit-TOR (HEAT) repeat protein family, and are required as scaffolds for the formation of the heterotrimeric PP2A complex (2).…”

Section: Introductionmentioning

confidence: 99%

Infrequent mutations of the PPP2R1A and PPP2R1B genes in patients with ovarian cancer

Wang

Zou

Liu

et al. 2013

Molecular Medicine Reports

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Abstract. Protein phosphatase 2, regulatory subunit A, α (PPP2R1A) and β (PPP2R1B) are paralogous subunits of the heterotrimeric protein phosphatase 2 (PP2A) holoenzyme that catalyzes the dephosphorylation of target substrate proteins. Subtype-specific PPP2R1A mutations have been frequently observed in ovarian and endometrial cancer. Mutations in the paralogous genes were frequently observed in human malignancies. Thus, the present study aimed to analyze the mutation frequencies of the paralogous PPP2R1A and PPP2R1B genes in patients with primary and secondary ovarian cancer. A total of 251 patients with primary (n=234) and secondary (n=17) ovarian cancer were analyzed for the presence of PPP2R1A and PPP2R1B mutations by direct sequencing. For PPP2R1A, a heterozygous, somatic mutation (c.771G>T, p.W257C) was identified in 1 out of 37 patients (2.7%) with primary ovarian endometrioid carcinoma. The mutant sample was that of a 46-year-old female, who was also diagnosed with ectopic endometriosis in the benign ovary. No PPP2R1A mutations were detected in the remaining 250 patients with ovarian cancer. For PPP2R1B, no mutations were detected in our samples. The results of this study suggested that PPP2R1A mutations are less common in Chinese patients with ovarian cancer when compared with European and American patients. Furthermore, our study also supported previous observations that PPP2R1B mutations were absent in ovarian cancer, suggesting that PPP2R1B mutations are not actively involved in the pathogenesis of ovarian cancer. IntroductionProtein phosphatase 2, regulatory subunit A, α (PPP2R1A) and β (PPP2R1B) are paralogous subunits of the heterotrimeric protein phosphatase 2 (PP2A) holoenzyme, which catalyzes the dephosphorylation of target substrate proteins (www.ensembl.org) (1). PPP2R1A and PPP2R1B belong to the Huntington-elongation-A subunit-TOR (HEAT) repeat protein family, and are required as scaffolds for the formation of the heterotrimeric PP2A complex (2). PPP2R1A and PPP2R1B each contain 15 tandemly repeated HEAT motifs. It has been previously demonstrated that the HEAT repeats 2-8 and 11-15 were involved in binding to the regulatory and catalytic subunits of PP2A, respectively (3). In addition, mutations located in the HEAT 2 and 11 motifs promoted tumorigenesis; the mutant PPP2R1A proteins were defective in binding to the regulatory and catalytic subunits of PP2A, resulting in a decrease in PP2A activity and thus facilitating tumor progression (4).A previous whole-exome sequencing attempt identified recurrent PPP2R1A mutations in 3 out of 42 patients (7.1%) with ovarian clear cell carcinoma (OCCC) (5). Subsequent studies confirmed this finding and also revealed frequent PPP2R1A mutations in patients with ovarian endometrioid carcinoma (6-8). Additionally, a high frequency of PPP2R1A mutations was also identified in several subtypes of endometrial carcinoma, with the highest frequency demonstrated in the serous subtype (6-9). Furthermore, previous studies revealed that PPP2R1A mutations were present ...

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Determinants for Substrate Specificity of Protein Phosphatase 2A

Cited by 82 publications

References 71 publications

Atypical Protein Phosphatase 2A Gene Families Do Not Expand via Paleopolyploidization

Atypical Protein Phosphatase 2A Gene Families Do Not Expand via Paleopolyploidization

A PP6-Type Phosphatase Holoenzyme Directly Regulates PIN Phosphorylation and Auxin Efflux in Arabidopsis

Infrequent mutations of the PPP2R1A and PPP2R1B genes in patients with ovarian cancer

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