Disease relevance of PPP1R12A

• Analysis of the expression and phosphorylation of Ca(2+)-sensitizing proteins (MYPT1 and CPI-17) in vessels from rats and patients with cirrhosis suggested decreased Ca2+ sensitivity [1].
• This phosphorylation of MYPT1 was significantly inhibited by application of Y-27632 and by pretreatment with pertussis toxin [2].
• We tested the hypothesis that hypoxia induces Ca(2+)-desensitizing hypoxic relaxation via dephosphorylation of p-MYPT1, consequently increasing MLCP activity and thus decreasing p-MRLC. alpha-Toxin-permeabilized PCASM pretreated with ATPgammaS did not relax in response to hypoxia [3].
• In a model of portal hypertension we previously showed dynamic changes in the expression of MYPT1 isoforms in the portal vein and upstream mesenteric artery [4].
• To optimise breast cancer screening protocols, risk (induction of fatal tumors) versus benefit (reduction in the number of fatal tumors) analyses are performed for a simulated stable Swedish female population, using the Model for evaluation of Breast cancer Screening (MBS) [5].

Psychiatry related information on PPP1R12A

• The study was descriptive in design and used a semistructured interview format with four open-ended questions and a numerical self-assessment of dyspnea using the Modified 0-10 Borg Scale (MBS) [6].

High impact information on PPP1R12A

• It is shown here that cGKIalpha is targeted to the smooth muscle cell contractile apparatus by a leucine zipper interaction with the myosin-binding subunit (MBS) of myosin phosphatase [7].
• Uncoupling of the cGKIalpha-MBS interaction prevents cGMP-dependent dephosphorylation of myosin light chain, demonstrating that this interaction is essential to the regulation of vascular smooth muscle cell tone [7].
• The guanosine triphosphate (GTP)-bound, active form of RhoA (GTP.RhoA) specifically interacted with the myosin-binding subunit (MBS) of myosin phosphatase, which regulates the extent of phosphorylation of MLC [8].
• The crystal structure of the PP1 catalytic subunit in complex with the targeting subunit MYPT1 indicates that there is also scope for intimate phosphatase regulation by scaffold proteins [9].
• We propose that CPI-17 binds at the PP1 active site where it is dephosphorylated, but association of MYPT1 with PP1C allosterically retards this hydrolysis, resulting in formation of a complex of MYPT1.PP1C.P-CPI-17, leading to an increase in smooth muscle contraction [10].

Chemical compound and disease context of PPP1R12A

• The new automated Enzymun-Test anti-HBc Plus for the detection of antibodies to hepatitis B virus (HBV) core antigen (anti-HBc) after pretreatment with reducing agents dithiothreitol (25 degrees C; + DTT) or potassium bisulfite (37 degrees C; + MBS) was evaluated by testing 571 serum and plasma samples [11].

Biological context of PPP1R12A

• We tested the hypothesis that the uterine quiescence observed during gestation is mediated by an increase in RND protein expression inhibiting RHOA-ROCK-mediated PPP1R12A phosphorylation [12].
• The myosin phosphatase (MP) composed of the catalytic subunit of type 1 protein phosphatase and myosin phosphatase target subunit isoform 1 (MYPT1) was identified as the major serine/threonine phosphatase component in the platelet-cytoskeleton fraction [13].
• Myosin phosphatase targeting subunit 1 affects cell migration by regulating myosin phosphorylation and actin assembly [14].
• Fluorescence in situ hybridization analysis placed the human MYPT1 gene on chromosome 12q15-q21 [15].
• Localization of the gene coding for myosin phosphatase, target subunit 1 (MYPT1) to human chromosome 12q15-q21 [15].

Anatomical context of PPP1R12A

• A significant increase of RND2 and RND3 protein expression was observed in pregnant relative to nonpregnant myometrium associated with a loss of PPP1R12A phosphorylation [12].
• Integrin-linked kinase phosphorylates the myosin phosphatase target subunit at the inhibitory site in platelet cytoskeleton [13].
• HeLa cells contain MYPT1 in addition to a newly identified human variant 2 containing an internal deletion [14].
• The reintroduction of MYPT1 or variant 2 in siRNA-treated cells decreased stress fibers and focal adhesions [14].
• The inhibitory effect of sildenafil (10 microM) on MYPT1 phosphorylation was demonstrated by the loss of actin stress fibres in vascular smooth muscle cells [16].

Associations of PPP1R12A with chemical compounds

• A combination of the Rho-kinase inhibitor Y-27632 and GF109203X led to a further decrease in STA(2)-induced MLC(20) phosphorylation, mainly because of a significant inhibition of MBS phosphorylation at Thr-696 [17].
• Treatment of intact platelets with thrombin or the stable thromboxane A(2) analog STA(2) resulted in increased phosphorylation of both CPI and MBS at Thr-696, whereas phorbol myristate acetate (PMA) and the Ca(++) ionophore ionomycin only induced CPI phosphorylation [17].
• These results indicate that both Ins(1,4,5)P(3)-induced Ca(2+) release and Rho-kinase-induced MYPT1 phosphorylation at Thr853 play pivotal roles in MLC phosphorylation of cultured VSMCs where either Ca(2+)-influx or CPI-17-MLCP signaling is downregulated [18].
• Chronic fasudil (30 mg kg(-1) day(-1); 14 days) and sildenafil (25 mg kg(-1) day(-1); 14 days) treatments reduced PH and pulmonary cardiovascular remodelling, and inhibited the MYPT1 phosphorylation in pulmonary artery from hypoxic rats by 82.3+/-3% (n=4) and by 76.6+/-2% (n=4), respectively [16].
• Forskolin, dbcAMP, and isoproterenol inhibited KCl-induced Rho activation and phosphorylation of MYPT1 and CPI-17 [19].

Enzymatic interactions of PPP1R12A

• Myotonic dystrophy protein kinase phosphorylates the myosin phosphatase targeting subunit and inhibits myosin phosphatase activity [20].

Regulatory relationships of PPP1R12A

• Both Y27632 and a negative dominant construct of RhoA inhibited phosphorylation of MYPT and CPI-17 [21].
• Inhibition of PKCs or calphostin C or selective inhibition of PKC-alpha by negative dominant constructs inhibited phosphorylation of MYPT and CPI-17 [21].
• Mutant forms of p116Rip that fail to oligomerize or bind to MBS are still capable of inhibiting SRF activity [22].
• Down-regulation of PI3K-C2alpha expression by siRNA (small interfering RNA) inhibited contraction and phosphorylation of MYPT1 and MLC in VSM cells [23].

Other interactions of PPP1R12A

• By modulating and targeting the catalytic phosphatase subunit to its substrates, MYPT1, MYPT2, and MBS85 regulate various contractile processes in muscle and non-muscle cells [24].
• MYPT1 contains a phosphorylation site, Thr-695, involved in the inhibition of MP in a RhoA/Rho kinase-dependent manner [13].
• Basal promoter activity was due to the GC-rich region that contained one Sp1 transcription factor binding site, thus demonstrating that the MYPT1 gene is a housekeeping gene [25].
• The sustained response is mediated via selective ETA-dependent phosphorylation of MYPT1 [26].
• Ca(2+) sensitization induced by activation of G protein-coupled receptors acting through RhoA involves phosphorylation of Thr-696 (of the human isoform) of the myosin targeting subunit (MYPT1) of SMPP-1M inhibiting activity [27].

Analytical, diagnostic and therapeutic context of PPP1R12A

• 2. Radiation hybrid mapping has shown that the human MYPT1 gene is located very near the highly polymorphic marker CHLC.GATA65A12, which lies between D12S350 and D12S106 [15].
• Molecular cloning and analysis of the 5'-flanking region of the human MYPT1 gene [25].
• RT-PCR and Western blot analyses were performed to determine RhoA, ROCK-II, CPI-17, MYPT1, and myosin light-chain 20 (MLC(20)) [28].
• In control cells MYPT1 was localized in the cytoplasm and in the nucleus, as determined by confocal microscopy [29].
• Psychotropic drug intake was assessed in participants aged 30-69 years of two identically designed studies (cross-sectional studies based on random samples), the Munich Blood Pressure Study (MBS I 1980/81) and the Luebeck Blood Pressure Study (LBS 1984) [30].

References