Phosphatase Subfamily PHLPP - Revision history

Gerard at 05:28, 14 March 2017

2017-03-14T05:28:25Z

Mark: /* PH domain of PHLPP */

2017-03-09T19:38:13Z

‎PH domain of PHLPP

Gerard at 20:24, 4 March 2017

2017-03-04T20:24:56Z

Gerard at 00:47, 4 March 2017

2017-03-04T00:47:50Z

Gerard at 00:47, 4 March 2017

2017-03-04T00:47:19Z

Gerard: /* Domain */

2016-09-08T00:59:16Z

‎Domain

Mark: /* Evolution */

2015-08-25T19:39:57Z

‎Evolution

Mark: /* Evolution */

2015-08-25T19:39:44Z

‎Evolution

Mark at 19:38, 25 August 2015

2015-08-25T19:38:58Z

Mark at 19:38, 25 August 2015

2015-08-25T19:38:45Z

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 [[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM]]: [[Phosphatase_Family_PPM|Family PPM]]: [[Phosphatase_Subfamily_PHLPP|Subfamily PHLPP]]
-PHLPP (PH domain leucine-rich repeat protein phosphatases) phosphatases regulate Akt, PKC and other AGC kinases through dephosphorylation of their hydrophobic motifs
+PHLPP (PH domain leucine-rich repeat protein phosphatases) phosphatases regulate Akt, PKC and other AGC kinases through dephosphorylation of their hydrophobic motifs.
 === Evolution ===
-The PHLPP subfamily is found across bilateria. Human has two members, PHLPP1/SCOP andPHLPP2, which most likely originated from vertebrate whole genome duplication. A likely homolog exists in fungi, where it is fused to adenylate cyclase. In Saccharomyces CYR1, it is the only adenylate cylcase gene in the genome.
+The PHLPP subfamily is found across bilateria. Human has two members, PHLPP1/SCOP and PHLPP2, which most likely originated from vertebrate whole genome duplication. A likely homolog exists in fungi, where it is fused to adenylate cyclase (CYR1 in Saccharomyces cerevisiae).
 === Domain ===
-The PHLPP subfamily has a N-terminal putative ras-binding domain (RBD), followed by a PH domain, several leucine rich repeats, a phosphatase domain, and (in vertebates) a C-terminal PDZ-domain binding motif. Ecdysozoa (e.g. Drosophila and Caenorhabditis) have a divergent PH domain that scores poorly on HMM or PSSM profiles from public databases (see [[Phosphatase_Subfamily_PHLPP#PH_domain_of_PHLPP|technical note]]), and Muscomorpha, including Drosophila, have lost the PH and RBD, while within nematodes, Caenorhabditids have also lost the RBD.
+The PHLPP subfamily has a N-terminal putative ras-association (RA) domain, followed by a PH domain, several leucine rich repeats, a phosphatase domain, and (in vertebates) a C-terminal PDZ-domain binding motif. Ecdysozoa (e.g. Drosophila and Caenorhabditis) have a divergent PH domain that scores poorly on HMM or PSSM profiles from public databases (see [[Phosphatase_Subfamily_PHLPP#PH_domain_of_PHLPP|technical note]]), and Muscomorpha, including Drosophila, have lost the PH and RBD, while within nematodes, Caenorhabditids have also lost the RBD.
 === Functions ===

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 === Technical notes ===
 ===== PH domain of PHLPP =====
-PHLPPs of deuterostomes (e.g. human) and lophotrochozoa have the PH domain, as detected by HMM or PSSM profiles from Pfam and/or NCBI CDD database. However, we cannot find PH domain in PHLPPs of most ecdysozoa (e.g. Drosophila and Caenorhabditis). When PSI-BLASTing the full sequence of human PHLPP, we found the PH domain in ''Loa loa'' PHLPP. We then PSI-BLASTed the PH domain in ''Loa loa'' PHLPP and found the PH domains in other nematode PHLPPs. However, we do not find the hits from arthropods. We looked in the domain combination of Drosophila melanogaster PHLPP, which has LRRs and phosphatase domains started from ~100 aa. Because the PH domain is adjacent to LRRs on the N-terminal side, we therefore hypothesized there might a PH domain located somewhere from 1 to 100 aa. We PSI-BLASTed the region and confirmed its sequence similarity to the PH domain of human PHLPP. In sum, the PH domains in arthropods and nematodes are divergent.
+PHLPPs of deuterostomes (e.g. human) and lophotrochozoa have the PH domain, as detected by HMM or PSSM profiles from Pfam and/or NCBI CDD database. However, we cannot find PH domain in PHLPPs of most ecdysozoa (e.g. Drosophila and Caenorhabditis). When PSI-BLASTing the full sequence of human PHLPP, we found the PH domain in ''Loa loa'' PHLPP. We then PSI-BLASTed the PH domain in ''Loa loa'' PHLPP and found the PH domains in other nematode PHLPPs. However, we do not find the hits from arthropods.

@@ Line 2: / Line 2: @@
 [[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM]]: [[Phosphatase_Family_PPM|Family PPM]]: [[Phosphatase_Subfamily_PHLPP|Subfamily PHLPP]]
-PHLPP stands for PH domain and leucine rich repeat protein phosphatase.
+PHLPP (PH domain leucine-rich repeat protein phosphatases) phosphatases regulate Akt, PKC and other AGC kinases through dephosphorylation of their hydrophobic motifs
 === Evolution ===
-The PHLPP subfamily is found across bilateria. Human has two members, PHLPP1/SCOP andPHLPP2, which most likely originated from vertebrate whole genome duplication. The canonical PH domain as defined by HMM or PSSM profiles from public database are found in most PHLPPs of deuterostomes and lophotrochozoa PHLPPs. However, the ecdysozoa (e.g. Drosophila and Caenorhabditis) PHLPPs have a PH domain quite divergent from the canonical PH domain (see [[Phosphatase_Subfamily_PHLPP#PH_domain_of_PHLPP|technical note]]). Since both ecdysozoa and lophotrochozoa are protostomes, the PH domain diverged after ecdysozoa split from protostomes.
+The PHLPP subfamily is found across bilateria. Human has two members, PHLPP1/SCOP andPHLPP2, which most likely originated from vertebrate whole genome duplication. A likely homolog exists in fungi, where it is fused to adenylate cyclase. In Saccharomyces CYR1, it is the only adenylate cylcase gene in the genome.
 === Domain ===
-The PHLPP subfamily has a N-terminal PH domain, followed by several leucine rich repeats, phosphatase domain, and a C-terminal PDZ-domain binding motif.
+The PHLPP subfamily has a N-terminal putative ras-binding domain (RBD), followed by a PH domain, several leucine rich repeats, a phosphatase domain, and (in vertebates) a C-terminal PDZ-domain binding motif. Ecdysozoa (e.g. Drosophila and Caenorhabditis) have a divergent PH domain that scores poorly on HMM or PSSM profiles from public databases (see [[Phosphatase_Subfamily_PHLPP#PH_domain_of_PHLPP|technical note]]), and Muscomorpha, including Drosophila, have lost the PH and RBD, while within nematodes, Caenorhabditids have also lost the RBD.
 === Functions ===
-The PHLPP subfamily dephosphorylates kinases of AGC group at serines in hydrophobic motif.
+PHLPP dephosphorylates [http://kinase.com/wiki/index.php/Kinase_Group_AGC AGC group] kinases at serines in their hydrophobic motif, in particular members of the Akt and PKC families.
-* PHLPP1 and PHLPP2 dephosphorylates and inactivates kinases of AKT/PKB family  at Ser-473 of human AKT1 <cite>Gao05, Brognard07</cite>. PHLPP1 prefers to dephosphorylate AKT2 and PHLPP2 prefers AKT3 <cite>Brognard07</cite>. The position Ser-473 located in hydrophobic motif is conserved across bilateria and among the three human members. It is also found in one sponge AKT, but not all three sponge AKTs (see [http://kinase.com/web/current/kinbase/genes/Family/Akt/alignment/protein/view alignment in KinBase]).
+* PHLPP1 and PHLPP2 dephosphorylate and inactivate Akt kinases  at Ser-473 of human AKT1 <cite>Gao05, Brognard07</cite>. PHLPP1 prefers to dephosphorylate AKT2 and PHLPP2 prefers AKT3 <cite>Brognard07</cite>. The position Ser-473 located in the hydrophobic motif is conserved across bilateria and among the three human members. It is also found in one sponge AKT, but absent from other sponge AKTs (see [http://kinase.com/web/current/kinbase/genes/Family/Akt/alignment/protein/view alignment in KinBase]).
-* The PHLPP subfamily also dephosphorylates PKC at Ser-660 of human PKC-beta <cite>Gao08</cite>. The position Ser-660 located in hydrophobic motif is conserved across metazoa (replaced by Thr in sea urchin) (see [http://kinase.com/web/current/kinbase/genes/Subfamily/PKCa/alignment/protein/view KinBase]).
+* PHLPP also dephosphorylates PKC at Ser-660 of human PKC-beta <cite>Gao08</cite>, also in the hydrophobic motif. This motif is conserved across metazoa (replaced by Thr in sea urchin) (see [http://kinase.com/web/current/kinbase/genes/Subfamily/PKCa/alignment/protein/view KinBase]).
-* The PHLPP subfamily also dephosphorylates S6 kinase <cite>Liu11</cite>.
+* PHLPP also dephosphorylates S6 kinase <cite>Liu11</cite>.
 Loss of PHLPP can increase the level of phosphorylated [http://en.wikipedia.org/wiki/Survivin Survivin], a member of the inhibitor of apoptosis (IAP) family, in gallbladder carcinoma (GBC) cells <cite>Qiu15</cite>. But, it is unclear whether PHLPP directly dephosphorylates Survivin.
-PHLPP1 and PHLPP2 are implicated in different kinds of cancers, such as colon cancer <cite>Liu09</cite>, hypopharyngeal squamous cell carcinomas <cite>Zhou15</cite>.
+PHLPP1 and PHLPP2 are implicated in different kinds of cancers, including colon cancer <cite>Liu09</cite> and hypopharyngeal squamous cell carcinomas <cite>Zhou15</cite>.
 === References ===

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 __NOTOC__
-[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM (PP2C)]]: [[Phosphatase_Family_PPM|Family PPM (PP2C)]]: [[Phosphatase_Subfamily_PHLPP|Subfamily PHLPP]] (PH domain and leucine rich repeat protein phosphatase)
+[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM]]: [[Phosphatase_Family_PPM|Family PPM]]: [[Phosphatase_Subfamily_PHLPP|Subfamily PHLPP]]
 PHLPP stands for PH domain and leucine rich repeat protein phosphatase.

← Older revision		Revision as of 00:47, 4 March 2017
Line 1:		Line 1:
		+	__NOTOC__
	[[Phosphatase classification\|Phosphatase Classification]]: [[Phosphatase_Fold_PPM\|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM\|Superfamily PPM (PP2C)]]: [[Phosphatase_Family_PPM\|Family PPM (PP2C)]]: [[Phosphatase_Subfamily_PHLPP\|Subfamily PHLPP]] (PH domain and leucine rich repeat protein phosphatase)		[[Phosphatase classification\|Phosphatase Classification]]: [[Phosphatase_Fold_PPM\|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM\|Superfamily PPM (PP2C)]]: [[Phosphatase_Family_PPM\|Family PPM (PP2C)]]: [[Phosphatase_Subfamily_PHLPP\|Subfamily PHLPP]] (PH domain and leucine rich repeat protein phosphatase)

@@ Line 4: / Line 4: @@
 === Evolution ===
-The PHLPP subfamily is found across bilateria. Human has two members, PHLPP1/SCOP andPHLPP2, which most likely originated from vertebrate whole genome duplication. The canonical PH domain as defined by HMM or PSSM profiles from public database are found in most PHLPPs of deuterostomes and lophotrochozoa PHLPPs. However, the ecdysozoa (e.g. Drosophila and Caenorhabditis) PHLPPs have a PH domain quite divergent from the canonical PH domain (see [#Technical_notes]). Since both ecdysozoa and lophotrochozoa are protostomes, the PH domain diverged after ecdysozoa split from protostomes.
+The PHLPP subfamily is found across bilateria. Human has two members, PHLPP1/SCOP andPHLPP2, which most likely originated from vertebrate whole genome duplication. The canonical PH domain as defined by HMM or PSSM profiles from public database are found in most PHLPPs of deuterostomes and lophotrochozoa PHLPPs. However, the ecdysozoa (e.g. Drosophila and Caenorhabditis) PHLPPs have a PH domain quite divergent from the canonical PH domain (see [Phosphatase_Subfamily_PHLPP#PH_domain_of_PHLPP|technical note]). Since both ecdysozoa and lophotrochozoa are protostomes, the PH domain diverged after ecdysozoa split from protostomes.
 === Domain ===

← Older revision		Revision as of 19:38, 25 August 2015
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−	~~__NOTOC__~~
	[[Phosphatase classification\|Phosphatase Classification]]: [[Phosphatase_Fold_PPM\|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM\|Superfamily PPM (PP2C)]]: [[Phosphatase_Family_PPM\|Family PPM (PP2C)]]: [[Phosphatase_Subfamily_PHLPP\|Subfamily PHLPP]] (PH domain and leucine rich repeat protein phosphatase)		[[Phosphatase classification\|Phosphatase Classification]]: [[Phosphatase_Fold_PPM\|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM\|Superfamily PPM (PP2C)]]: [[Phosphatase_Family_PPM\|Family PPM (PP2C)]]: [[Phosphatase_Subfamily_PHLPP\|Subfamily PHLPP]] (PH domain and leucine rich repeat protein phosphatase)

@@ Line 5: / Line 5: @@
 === Evolution ===
-The PHLPP subfamily is found across bilateria. Human has two members, PHLPP1/SCOP andPHLPP2, which most likely originated from vertebrate whole genome duplication. Human PHLPPs have a PH domain, which is also found in other deuterostome PHLPPs, as well as lophotrochozoa PHLPPs, by BLASTing human PH domain against NR database. However, it is absent from ecdysozoa (e.g. Drosophila and Caenorhabditis). Since both ecdysozoa and lophotrochozoa are protostomes, it is most probably that the PHLPP in bilateral ancestor had PH domain, but it was lost in ecdysozoa.
+The PHLPP subfamily is found across bilateria. Human has two members, PHLPP1/SCOP andPHLPP2, which most likely originated from vertebrate whole genome duplication. The canonical PH domain as defined by HMM or PSSM profiles from public database are found in most PHLPPs of deuterostomes and lophotrochozoa PHLPPs. However, the ecdysozoa (e.g. Drosophila and Caenorhabditis) PHLPPs have a PH domain quite divergent from the canonical PH domain (see [#Technical_notes]). Since both ecdysozoa and lophotrochozoa are protostomes, the PH domain diverged after ecdysozoa split from protostomes.
 === Domain ===
@@ Line 33: / Line 33: @@
 #Zhou15 pmid=25793736
 </biblio>