Phosphatase Subfamily PPM1A - Revision history

Gerard: /* Domains */

2017-03-24T19:10:41Z

‎Domains

Gerard: /* Domains */

2017-03-24T18:59:20Z

‎Domains

Gerard: /* Budding yeast PTC2, PTC3 and PTC4 */

2017-03-24T17:12:40Z

‎Budding yeast PTC2, PTC3 and PTC4

Gerard at 17:11, 24 March 2017

2017-03-24T17:11:04Z

Mark: /* Different functions of PPM1A and PPM1B */

2016-04-29T20:22:18Z

‎Different functions of PPM1A and PPM1B

Mark: /* Domains */

2015-06-18T21:51:41Z

‎Domains

Mark: /* Domains */

2015-06-18T21:51:27Z

‎Domains

Mark: /* References */

2015-06-08T20:36:33Z

‎References

Mark: /* Fruit fly alph (alphabet): negatively regulates RAS/MAPK and SAPK/JNK */

2015-06-08T20:30:14Z

‎Fruit fly alph (alphabet): negatively regulates RAS/MAPK and SAPK/JNK

Mark: /* Common substrates of human PPM1A and PPM1B */

2015-06-08T20:22:02Z

‎Common substrates of human PPM1A and PPM1B

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 === Domains ===
-The PPM1A subfamily has the phosphatase domain and a signature C-terminal domain next to catalytic domain, [http://pfam.xfam.org/family/PP2C_C PP2C_C] in Pfam. The PP2C_C domain consists of three antiparallel alpha helices, one of which packs against two corresponding alpha-helices of the phosphatase domain. The C-terminal domain does not seem to play a role in catalysis, but it may provide protein substrate specificity due to the cleft that is created between it and the catalytic domain. The PP2C_C domain is only present in PPM1A subfamily, and may be absent from Monosiga and yeast homologs, which have no sequence similarity in this region. Human PPM1A and PPM1N have a predicted nuclear localization signal (NLS) at N-terminal. PPM1As from other organisms have weak NLS by prediction.
+The PPM1A subfamily has the phosphatase domain and a signature C-terminal domain next to catalytic domain, [http://pfam.xfam.org/family/PP2C_C PP2C_C] in Pfam. The PP2C_C domain consists of three antiparallel alpha helices, one of which packs against two corresponding alpha-helices of the phosphatase domain. The C-terminal domain does not seem to play a role in catalysis, but it may provide protein substrate specificity due to the cleft that is created between it and the catalytic domain. The PP2C_C domain is only present in PPM1A subfamily, and may be absent from Monosiga and yeast homologs, which have no sequence similarity in this region (and PTC4 has no sequence after the phosphatase domain). Human PPM1A and PPM1N have a predicted nuclear localization signal (NLS) at N-terminal. PPM1As from other organisms have weak NLS by prediction.
 === Functions ===

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 === Domains ===
-The PPM1A subfamily has the phosphatase domain and a signature C-terminal domain next to catalytic domain, [http://pfam.xfam.org/family/PP2C_C PP2C_C] in Pfam. The PP2C_C domain consists of three antiparallel alpha helices, one of which packs against two corresponding alpha-helices of the phosphatase domain. The C-terminal domain does not seem to play a role in catalysis, but it may provide protein substrate specificity due to the cleft that is created between it and the catalytic domain. The PP2C_C domain is only present in PPM1A subfamily. Human PPM1A and PPM1N have a predicted nuclear localization signal (NLS) at N-terminal. PPM1As from other organisms have weak NLS by prediction.
+The PPM1A subfamily has the phosphatase domain and a signature C-terminal domain next to catalytic domain, [http://pfam.xfam.org/family/PP2C_C PP2C_C] in Pfam. The PP2C_C domain consists of three antiparallel alpha helices, one of which packs against two corresponding alpha-helices of the phosphatase domain. The C-terminal domain does not seem to play a role in catalysis, but it may provide protein substrate specificity due to the cleft that is created between it and the catalytic domain. The PP2C_C domain is only present in PPM1A subfamily, and may be absent from Monosiga and yeast homologs, which have no sequence similarity in this region. Human PPM1A and PPM1N have a predicted nuclear localization signal (NLS) at N-terminal. PPM1As from other organisms have weak NLS by prediction.
 === Functions ===

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 ===== Budding yeast PTC2, PTC3 and PTC4 =====
-As mentioned above, budding yeast has three PPM1As: PTC2, PTC3 and PTC4. Their functions are reviewed in table 1 in <cite>Sharmin14</cite> and in <cite>Arino11</cite>. In brief, PTC2 and PTC3 (but not PTC4) can directly dephosphorylate Cdc28 at Thr-169 <cite>Cheng99</cite>. In addition, all the three phosphatases are involved in high osmolarity glycerol (HOG) pathway, particularly PTC2 and PTC3 can directly dephosphorylate the [http://kinase.com/wiki/index.php/Kinase_Subfamily_p38 p38 kinase], Hog1 <cite>Gonzalez06</cite>. PTC2 can also dephosphorylate Ire1 to downregulate endoplasmic reticulum (ER) unfolded protein response <cite>Welihinda98</cite>.
+The three yeast PPM1As, PTC2, PTC3 and PTC4 are reviewed in table 1 in <cite>Sharmin14</cite> and in <cite>Arino11</cite>. PTC2 and PTC3 (but not PTC4) can dephosphorylate Cdc28 at Thr-169 <cite>Cheng99</cite>. All three phosphatases are involved in high osmolarity glycerol (HOG) pathway, particularly PTC2 and PTC3 can directly dephosphorylate the [http://kinase.com/wiki/index.php/Kinase_Subfamily_p38 p38 kinase], Hog1 <cite>Gonzalez06</cite>. PTC2 can also dephosphorylate Ire1 to downregulate endoplasmic reticulum (ER) unfolded protein response <cite>Welihinda98</cite>.
 === References ===

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 [[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM (PP2C)]]: [[Phosphatase_Family_PPM|Family PPM (PP2C)]]: [[Phosphatase_Subfamily_PPM1A|Subfamily PPM1A]]
 === Evolution ===
-The PPM1A subfamily is found across [[Phosphatase_Glossary#Holozoa|holozoa]] by sequence similarity. Budding yeast PTC2, PTC3 and PTC4 are inferred to be PPM1As, because they have the same substrate with holozoa PPM1A, human CDK2/yeast Cdc28.
+The PPM1A subfamily is found across opisthokonts. Budding yeast PTC2, PTC3 and PTC4 are inferred to be PPM1As, because they have the same substrate with holozoa PPM1A, human CDK2/yeast Cdc28.
 Human has three members: PPM1A, PPM1B and PPM1N. PPM1A and PPM1B arose by gene duplication in jawed vertebrates, but not through whole-genome duplication, as they do not locate in the same [[Phosphatase_Glossary#Double-conserved_synteny|double-conserved synteny]] (see [[Phosphatase_Glossary#Genomicus|Genomicus]]). Human PPM1N probably emerged in placentals and was lost by independent evolutionary events in different lineages, as implied by [http://resdev.gene.com/gOrtholog/view/cluster/MC0033446/overview internal orthology database] and BLAST NR database. For BLAST, human PPM1N was defined as the hits that have a better (lower) E-values than human PPM1A and PPM1B. Thus, all three human members, as well as other jawed vertebrate PPM1As, originated from a single ancestral gene. The PPM1A subfamily is also found in monosiga. Thus, the subfamily is most likely to emerge in [[Phosphatase_Glossary#Holozoa|holozoa]].
 === Domains ===
-The PPM1A subfamily has the phosphatase domain and a signature C-terminal domain next to catalytic domain, [http://pfam.xfam.org/family/PP2C_C PP2C_C] in Pfam. The PP2C_C domain consists of three antiparallel alpha helices, one of which packs against two corresponding alpha-helices of the N-terminal domain. The C-terminal domain does not seem to play a role in catalysis, but it may provide protein substrate specificity due to the cleft that is created between it and the catalytic domain. The PP2C_C domain is only present in PPM1A subfamily, but not other PPMs. Human PPM1A and PPM1N have a predicted nuclear localization signal (NLS) at N-terminal. PPM1As from other organisms have weak NLS by prediction, as well.
+The PPM1A subfamily has the phosphatase domain and a signature C-terminal domain next to catalytic domain, [http://pfam.xfam.org/family/PP2C_C PP2C_C] in Pfam. The PP2C_C domain consists of three antiparallel alpha helices, one of which packs against two corresponding alpha-helices of the phosphatase domain. The C-terminal domain does not seem to play a role in catalysis, but it may provide protein substrate specificity due to the cleft that is created between it and the catalytic domain. The PP2C_C domain is only present in PPM1A subfamily. Human PPM1A and PPM1N have a predicted nuclear localization signal (NLS) at N-terminal. PPM1As from other organisms have weak NLS by prediction.
 === Functions ===
-The PPM1A subfamily regulates different signaling pathways, such as MAPK, SAPK/JNK, NF-kappaB, TGF-beta pathways.
+PPM1A regulates different signaling pathways, such as MAPK, SAPK/JNK, NF-kappaB, TGF-beta pathways.
 ===== Common substrates of human PPM1A and PPM1B =====
 * IKKβ at Ser-177 and Ser-181. Both human PPM1A and PPM1B dephosphorylated IKKβ at Ser-177 and Ser-181 and termination of IKKβ-induced NF-κB activation <cite>Prajapati04, Sun09</cite>.
-* CDK at Thr-186 in the T-loop. Both PPM1A and PPM1B dephosphorylated CDK9 at Thr-186 in the T-loop <cite>Wang08</cite>. CDK9 is the catalytic subunit of a general RNA polymerase II elongation factor known as positive transcription elongation factor b (P-TEFb). The kinase function of P-TEFb requires phosphorylation of Thr-186 in the T-loop of Cdk9 to allow substrates to access the catalytic core of the enzyme <cite>Wang08</cite>.
+* CDK9 at Thr-186 in the T-loop. Both PPM1A and PPM1B dephosphorylated CDK9 at Thr-186 in the T-loop <cite>Wang08</cite>. CDK9 is the catalytic subunit of a general RNA polymerase II elongation factor known as positive transcription elongation factor b (P-TEFb). The kinase function of P-TEFb requires phosphorylation of Thr-186 in the T-loop of Cdk9 to allow substrates to access the catalytic core of the enzyme <cite>Wang08</cite>.
 * Moesin at Thr-588. Both PPM1A and PPM1B dephosphorylated the membrane-F-actin linking protein moesin at Thr-588, which is phosphorylated during activation of platelets <cite>Hishiya99</cite>.
 * CDK2 at Thr-160 <cite>Cheng00</cite>. Yeast PPM1As, PTC2 and PTC3 (but not PTC4), can dephosphorylate Cdc28, the ortholog of human CDK2, at the same site (Thr-169) <cite>Cheng99</cite>.
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 ===== Budding yeast PTC2, PTC3 and PTC4 =====
-As mentioned above, budding yeast has three PPM1As: PTC2, PTC3 and PTC4. Their functions are reviewed in table 1 in <cite>Sharmin14</cite> and in <cite>Arino11</cite>. In brief, PTC2 and PTC3 (but not PTC4) can directly dephosphorylate Cdc28 at Thr-169 <cite>Cheng99</cite>. In addition, all the three phosphatases are involved in high osmolarity glycerol (HOG) pathway, particularly PTC2 and PTC3 can directly dephosphorylate Hog1 <cite>Gonzalez06</cite>. PTC2 can also dephosphorylate Ire1 to down regulate endoplasmic reticulum (ER) unfolded protein response <cite>Welihinda98</cite>.
+As mentioned above, budding yeast has three PPM1As: PTC2, PTC3 and PTC4. Their functions are reviewed in table 1 in <cite>Sharmin14</cite> and in <cite>Arino11</cite>. In brief, PTC2 and PTC3 (but not PTC4) can directly dephosphorylate Cdc28 at Thr-169 <cite>Cheng99</cite>. In addition, all the three phosphatases are involved in high osmolarity glycerol (HOG) pathway, particularly PTC2 and PTC3 can directly dephosphorylate the [http://kinase.com/wiki/index.php/Kinase_Subfamily_p38 p38 kinase], Hog1 <cite>Gonzalez06</cite>. PTC2 can also dephosphorylate Ire1 to downregulate endoplasmic reticulum (ER) unfolded protein response <cite>Welihinda98</cite>.
 === References ===

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 * Axin. PPM1A formed a complex with Dvl, beta-catenin, and Axin. It dephosphorylated Axin, a negative regulator of WNT signaling, both in vitro and in vivo. The dephosphorylation resulted in decreasing Axin's half-life. PPM1A therefore is a positive regulator of WNT signal <cite>Strovel00</cite>.
 * PKCdelta. In addition to PPM1A, PP1 and PP2A (PP3) can also dephosphorylate PKCdelta, albeit lower specific activity <cite>Srivastava02</cite>.
-* SMAD1 and SMAD2/3 at SxS motif <cite>Lin06, Duan06</cite>. SMADs are critical players in TGF-beta signaling. The dephosphorylation increases their nuclear exporter activity.
+* SMAD1 and SMAD2/3 at SxS motif <cite>Lin06, Duan06</cite>. SMADs are critical players in TGF-beta signaling. The dephosphorylation increases their nuclear exporter activity. (Be careful: the Cell paper was flagged; the other paper is of the same author.)
 * RanBP3, nuclear exporter. PPM1A directly interacted with and dephosphorylated RanBP3 at Ser-58 both in vitro and in vivo. The dephosphorylation promoted RanBP3's ability to export Smad2/3 and terminate TGF-beta signaling <cite>Dai11</cite>.

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 <biblio>
 #Abraham15 pmid=25631048
 #Baril06 pmid=16600208
 #Baril06 pmid=19064708
@@ Line 68: / Line 69: @@
 #Duan06 pmid=16931515
 #Flajolet03 pmid=14663150
 #Hanada01 pmid=11104763
 #Hishiya99 pmid=10480873
@@ Line 75: / Line 77: @@
 #Ofek03 pmid=12514180
 #Prajapati04 pmid=14585847
 #Srivastava02 pmid=11959144
 #Strovel00 pmid=10644691
@@ Line 82: / Line 85: @@
 #Tasdelen13 pmid=23320500
 #Wang08 pmid=18829461
 #Yien12 pmid=22393050
 #Yoshizaki04 pmid=15016818
 #Zhao12 pmid=22750291
 </biblio>

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 PPM1N's function is unknown. It is generally expressed at low level across tissues except spleen (see RNA-seq data from [http://www.gtexportal.org/home/gene/PPM1N GTEx]).
-===== Fruit fly alph (alphabet): negatively regulates RAS/MAPK and SAPK/JNK =====
+===== Fruit fly alph: negatively regulates RAS/MAPK and SAPK/JNK =====
 Alphabet, the PPM1A in fruit fly, negatively regulates RAS/MAPK signaling in Drosophila <cite>Baril06</cite> and stress-activated protein kinase (SAPK) <cite>Baril09</cite>. However, its substrates in these signaling pathways are unclear.
 === References ===