Disease relevance of PPM1A

• Adenovirus-2 early region IA protein synthesized in Escherichia coli extracts indirectly associates with DNA [1].
• Isoforms IA and III-PII had an identical N-terminal amino acid sequence which showed homologies to the N-terminal sequence of sialidases produced by Bacteroides fragilis SBT3182, another commensal enteric bacterium [2].
• RESULTS: As a complication after sphincterotomy, pancreatitis developed in one of eight patients (12.5%) in group IA, whereas cholangitis occurred in one of 22 (4.5%) and hemorrhage in one of 22 (4.5%) cases in group IB [3].
• Maternal transmission of Gs(alpha) mutations leads to AHO plus resistance to several hormones (e.g., parathyroid hormone) that activate Gs in their target tissues (pseudohypoparathyroidism type IA), while paternal transmission leads only to the AHO phenotype (pseudopseudohypoparathyroidism) [4].
• Liver and liver cell transplantation for glycogen storage disease type IA [5].

High impact information on PPM1A

• (2006) answer one of the long-standing questions in the TGFbeta field by identifying a phosphatase, PPM1A, that directly dephosphorylates Smad2 and Smad3 to limit their activation [6].
• PPM1A dephosphorylates and promotes nuclear export of TGFbeta-activated Smad2/3 [7].
• Smad-antagonizing activity of PPM1A is also observed during Nodal-dependent early embryogenesis in zebrafish [7].
• Accordingly, IpgD and PtdIns5P production specifically activates a class IA PI 3-kinase via a mechanism involving tyrosine phosphorylations [8].
• Isolation of a marker linked to the Charcot-Marie-Tooth disease type IA gene by differential Alu-PCR of human chromosome 17-retaining hybrids [9].

Biological context of PPM1A

• We now demonstrate that PP2C alpha, a major mammalian isoform, inhibits cell growth and activates the p53 pathway [10].
• In 293 cell clones, in which PP2C alpha expression is regulated by a tetracycline-inducible promoter, PP2C alpha overexpression led to G(2)/M cell cycle arrest and apoptosis [10].
• VSMC expressed all class IA PI3K isoforms, but microinjection experiments demonstrated that only the p110beta isoform was involved in chemotaxis [11].
• Assignment of the gene encoding magnesium-dependent protein phosphatase 1alpha (PPM1A) to human chromosome 14q22-->q23 and rat chromosome 6q24 by fluorescence in situ hybridization [12].
• Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils [13].

Anatomical context of PPM1A

• In addition, inhibition by IC87114 of the major class IA PI3K catalytic subunit expressed in lymphocytes, p110delta, blocked transition of DN to DP cells in embryonic day 14.5 fetal thymic organ culture without affecting cell viability [14].
• We found that the PP2C-like activity in HeLa cell extract, partially purified HeLa PP2C alpha and PP2C beta 2 isoforms, and the recombinant PP2Cs exhibited a comparable substrate preference for a phosphothreonine containing substrate, consistent with the conservation of threonine residues at the site of activating phosphorylation in CDKs [15].
• No mRNA for PP2C alpha was detected in resting or 1,25(OH)2D3-stimulated HL-60 cells [16].
• We showed recently that rhythmic arm movement significantly suppresses soleus H-reflex amplitude probably via modification of presynaptic inhibition of the IA afferent pathway [17].
• Crude cord blood samples yielded three isoforms: AFP-IA, IB, and II, with pIs 4.57 (52%), 4.27 (43%), and less than 4.00 (5%), respectively [18].

Associations of PPM1A with chemical compounds

• In this study, we have found that PPM1A, a metal ion-dependent protein serine/threonine phosphatase, physically interacts with and dephosphorylates Smad1 both in vitro and in vivo [19].
• Hydroxyapatite chromatography further resolved the most hydrophilic, isoform I, into isoforms IA and IB [2].
• The p85{alpha} Regulatory Subunit of Class IA Phosphoinositide 3-Kinase Regulates beta-Selection in Thymocyte Development [14].
• Isoform IB differed from IA and III in N-terminal amino acid sequence and in sensitivity to EDTA inhibition [2].
• Caffeine and theophylline also inhibit the intrinsic protein kinase activity of the class IA PI3Ks and DNA-dependent protein kinase, although with a much lower potency than that for the lipid kinase (IC(50) approximately 10 mm for p110 alpha, 3 mm for p110 beta, and 10 mm for DNA-dependent protein kinase) [20].

Enzymatic interactions of PPM1A

• Protein Serine/Threonine Phosphatase PPM1A Dephosphorylates Smad1 in the Bone Morphogenetic Protein Signaling Pathway [19].
• We recently discovered that PPM1A can dephosphorylate Smad2/3 at the C-terminal SXS motif, implicating a critical role for phosphatases in regulating TGF-beta signaling [21].

Regulatory relationships of PPM1A

• Furthermore, PP2C alpha induced the expression of endogenous p53 and the p53-responsive gene p21 [10].

Other interactions of PPM1A

• The role of PP2C alpha in p53 activation is discussed [10].
• Collectively, our study suggests that PPM1A plays an important role in controlling BMP signaling through catalyzing Smad dephosphorylation [19].
• Furthermore, enhanced beta-catenin signaling by coexpression of beta-catenin or PP2C alpha attenuate cell death [22].

Analytical, diagnostic and therapeutic context of PPM1A

• The most hydrophobic, isoform III, differed from IA and IB by a more acidic pH optimum, greater heat resistance, greater sensitivity to alkylating agents, and anomalous retardation during gel filtration chromatography [2].
• In order to facilitate the identification of novel and specific inhibitors of PP2C by random screening of compounds, and to further characterize this enzyme at the molecular level by site-directed mutagenesis and X-ray crystallography, we have expressed active recombinant human PP2C alpha (rPP2C alpha) in Escherichia coli [23].
• The results of quantitative PCR analysis indicated that the expression amount of group IA genes was around 100-300 times greater than that of group IB genes [24].
• Both mRNAs, encoding group IA (without a pancreatic loop) and group IB (with pancreatic loop), were detected from venom glands by Northern blot hybridization analysis and RT-PCR [24].
• Sequence analysis of 5'-upstream regions and a reporter gene assay of the genes (groups IA and IB) previously cloned showed that the functional sequence (411 bp) was inserted in the 5'-flanking region of the group IA PLA(2) genes [24].

References