Difference between revisions of "Phosphatase Subfamily PTPN23"
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| − | [[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTP|Family PTP]]: [[ | + | [[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTP|Family PTP]]: [[Phosphatase_Subfamily_PTPN23|Subfamily PTPN23]] (HD-PTP) |
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===Evolution=== | ===Evolution=== | ||
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===Domain === | ===Domain === | ||
| − | + | PTPN23 also known as Histidine Domain-Protein Tyrosine Phosphatase (HD-PTP), is a multidomain cytosolic member of the Bro1-domain-containing protein family. Besides its N-terminal Bro1 domain, HD-PTP has five other main structural domains: a V-domain with coiled-coil motifs, immediately after the Bro1 domain, a central unique proline-rich domain with numerous dispersed His residues (HD), a PTP-like domain (PTPc) and a second proline-rich domain towards the C-terminal end. Both the central and the C-terminal proline-rich domains have PEST motifs and appear to have disordered secondary structures <cite>Tanase10</cite>. | |
===Functions=== | ===Functions=== | ||
| − | + | ====== Is PTPN23 catalytically inactive? ====== | |
| + | PTPN23 was reported to be catalytically inactive, - no phosphatase activity toward tyrosine or lipid. It was proposed that serine at position 1452 within Cx5R catalytic motif caused the inactivity. Replacing serine with alanine, which is found in catalytically active PTPs, can restore the phosphatase activity <cite>Gingras09</cite>. | ||
| + | |||
| + | However, another study found SRC, E-cadherin, and beta-catenin are direct substrates of PTPN23 <cite>Lin11</cite>. But, yet another study showed that PTPN23 did not modulate the levels of Src phosphorylation both in vitro and in vivo <cite>Mariotti09</cite>. | ||
| + | |||
| + | ====== Interacting partners ====== | ||
| + | PTPN23 has below interacting partners, which functions in endosomal protein sorting and trafficking, apoptosis, and cell adhesion. Thus, PTPN23 is probably involved in these processes, too. | ||
| + | |||
| + | * [http://www.ncbi.nlm.nih.gov/gene?cmd=retrieve&dopt=default&rn=1&list_uids=128866 CHMP4B], charged multivesicular body protein 4B, a component of the endosomal sorting complex required for transport (ESCRT) complex III (ESCRT-III), which functions in the sorting of endocytosed cell-surface receptors into multivesicular endosomes. The interaction is mediated by BRO1 domain of PTPN23 <cite>Ichioka07</cite>. | ||
| + | |||
| + | * [http://en.wikipedia.org/wiki/TSG101 TSG101], Tumor susceptibility gene 101, a component of Endosomal Sorting Complex Required for Transport complex I (ESCRT-I). The main role of ESCRT-I is to recognize ubiquitinated cargo. The interaction is mediated by histidine domain of PTPN23 <cite>Ichioka07</cite>. | ||
| + | |||
| + | * Endophilin A1, an SH3 protein involved in receptor endocytosis. The interaction is mediated by histidine domain of PTPN23 <cite>Ichioka07</cite>. | ||
| + | |||
| + | * ALG-2, a protein important for apoptosis. The interaction is in a calcium-dependent manner <cite>Ichioka07</cite>. | ||
| + | |||
| + | * [http://en.wikipedia.org/wiki/GRB2 Grb2] and GrpL, two adapters of the Grb2 family which are essential for numerous signaling pathways. The interaction is mediated by histidine domain of PTPN23 <cite>Tanase10</cite>. | ||
| + | |||
| + | * Rab4. PTPN23 interacts with Rab4 and regulates the spatial distribution of Rab4 and integrin trafficking in human and fruit fly, therefore modulating cell adhesion and migration <cite>Chen12</cite>. | ||
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| + | * FAK, Focal Adhesion Kinase, a crucial regulator of cell migration. PTPN23 is a negative regulator of FAK phosphorylation, but it is unclear whether it dephosphorylates FAK in vivo <cite>Castiglioni07</cite>. | ||
| + | |||
| + | ====== PTPN23 and cancer ====== | ||
| + | Suppression of PTPN23 increased E-cadherin internalization, impaired early endosome trafficking of E-cadherin, induced the expression of mesenchymal proteins, and caused cell scattering. The activity of SRC and beta-catenin was elevated when PTPN23 was suppressed. Thus, PTPN23 may increase the activity of SRC and the phosphorylation status of the E-cadherin/beta-catenin signaling complex to promote tumor growth and invasive behavior in breast cancer <cite>Lin11</cite>. | ||
| + | |||
| + | PTPN23 is a tumor suppressor in testicular germ cell tumors (TGCTs) <cite>Tanaka13</cite>. | ||
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| + | PTPN23 is degraded by calpains in a calcium-dependent manner in T24 bladder carcinoma cells <cite>Castiglioni12</cite>. | ||
===References=== | ===References=== | ||
<biblio> | <biblio> | ||
| − | # | + | #Castiglioni07 pmid=17959146 |
| + | #Castiglioni12 pmid=22510412 | ||
| + | #Chen12 pmid=22825871 | ||
| + | #Ichioka07 pmid=17174262 | ||
| + | #Gingras09 pmid=19340315 | ||
| + | #Lin11 pmid=21724833 | ||
| + | #Mariotti09 pmid=18762272 | ||
| + | #Tanaka13 pmid=23843459 | ||
| + | #Tanase10 pmid=21179510 | ||
</biblio> | </biblio> | ||
| + | |||
| + | === Supplementary information === | ||
| + | The position in this page is numbered by PTPN23 sequence below: | ||
| + | |||
| + | >HsapP079_AA symbol=PTPN23 CC1:CC1:PTP:PTPN23 [Homo sapiens] | ||
| + | MRNRDSACAKDYASGWLGSLQLPAGRWHFSFPPVTSDFRHEGAGLGSWLSQQLQQLREWPGGRRVPAAMEAVPRMPMIWLDLKEAGDFHFQPAVKKFVLKNYGENPEAYNEELKKLELLRQNAVRVPRDFEGCSVLRKYLGQLHYLQSRVPMGSGQEAAVPVTWTEIFSGKSVAHEDIKYEQACILYNLGALHSMLGAMDKRVSEECAAGAFAYLREHFPQAYSVDMSRQILTLNVNLMLGQAQECLLEKSMLDNRKSFLVARISAQVVDYYKEACRALENPDTASLLGRIQKDWKKLVQMKIYYFAAVAHLHMGKQAEEQQKFGERVAYFQSALDKLNEAIKLAKGQPDTVQDALRFTMDVIGGKYNSAKKDNDFIYHEAVPALDTLQPVKGAPLVKPLPVNPTDPAVTGPDIFAKLVPMAAHEASSLYSEEKAKLLREMMAKIEDKNEVLDQFMDSMQLDPETVDNLDAYSHIPPQLMEKCAALSVRPDTVRNLVQSMQVLSGVFTDVEASLKDIRDLLEEDELLEQKFQEAVGQAGAISITSKAELAEVRREWAKYMEVHEKASFTNSELHRAMNLHVGNLRLLSGPLDQVRAALPTPALSPEDKAVLQNLKRILAKVQEMRDQRVSLEQQLRELIQKDDITASLVTTDHSEMKKLFEEQLKKYDQLKVYLEQNLAAQDRVLCALTEANVQYAAVRRVLSDLDQKWNSTLQTLVASYEAYEDLMKKSQEGRDFYADLESKVAALLERTQSTCQAREAARQQLLDRELKKKPPPRPTAPKPLLPRREESEAVEAGDPPEELRSLPPDMVAGPRLPDTFLGSATPLHFPPSPFPSSTGPGPHYLSGPLPPGTYSGPTQLIQPRAPGPHAMPVAPGPALYPAPAYTPELGLVPRSSPQHGVVSSPYVGVGPAPPVAGLPSAPPPQFSGPELAMAVRPATTTVDSIQAPIPSHTAPRPNPTPAPPPPCFPVPPPQPLPTPYTYPAGAKQPIPAQHHFSSGIPAGFPAPRIGPQPQPHPQPHPSQAFGPQPPQQPLPLQHPHLFPPQAPGLLPPQSPYPYAPQPGVLGQPPPPLHTQLYPGPAQDPLPAHSGALPFPSPGPPQPPHPPLAYGPAPSTRPMGPQAAPLTIRGPSSAGQSTPSPHLVPSPAPSPGPGPVPPRPPAAEPPPCLRRGAAAADLLSSSPESQHGGTQSPGGGQPLLQPTKVDAAEGRRPQALRLIERDPYEHPERLRQLQQELEAFRGQLGDVGALDTVWRELQDAQEHDARGRSIAIARCYSLKNRHQDVMPYDSNRVVLRSGKDDYINASCVEGLSPYCPPLVATQAPLPGTAADFWLMVHEQKVSVIVMLVSEAEMEKQKVARYFPTERGQPMVHGALSLALSSVRSTETHVERVLSLQFRDQSLKRSLVHLHFPTWPELGLPDSPSNLLRFIQEVHAHYLHQRPLHTPIIVHCSSGVGRTGAFALLYAAVQEVEAGNGIPELPQLVRRMRQQRKHMLQEKLHLRFCYEAVVRHVEQVLQRHGVPPPCKPLASASISQKNHLPQDSQDLVLGGDVPISSIQATIAKLSIRPPGGLESPVASLPGPAEPPGLPPASLPESTPIPSSSPPPLSSPLPEAPQPKEEPPVPEAPSSGPPSSSLELLASLTPEAFSLDSSLRGKQRMSKHNFLQAHNGQGLRATRPSDDPLSLLDPLWTLNKT | ||
Revision as of 05:54, 11 March 2015
Phosphatase Classification: Fold CC1: Superfamily CC1: Family PTP: Subfamily PTPN23 (HD-PTP)
Evolution
Domain
PTPN23 also known as Histidine Domain-Protein Tyrosine Phosphatase (HD-PTP), is a multidomain cytosolic member of the Bro1-domain-containing protein family. Besides its N-terminal Bro1 domain, HD-PTP has five other main structural domains: a V-domain with coiled-coil motifs, immediately after the Bro1 domain, a central unique proline-rich domain with numerous dispersed His residues (HD), a PTP-like domain (PTPc) and a second proline-rich domain towards the C-terminal end. Both the central and the C-terminal proline-rich domains have PEST motifs and appear to have disordered secondary structures [1].
Functions
Is PTPN23 catalytically inactive?
PTPN23 was reported to be catalytically inactive, - no phosphatase activity toward tyrosine or lipid. It was proposed that serine at position 1452 within Cx5R catalytic motif caused the inactivity. Replacing serine with alanine, which is found in catalytically active PTPs, can restore the phosphatase activity [2].
However, another study found SRC, E-cadherin, and beta-catenin are direct substrates of PTPN23 [3]. But, yet another study showed that PTPN23 did not modulate the levels of Src phosphorylation both in vitro and in vivo [4].
Interacting partners
PTPN23 has below interacting partners, which functions in endosomal protein sorting and trafficking, apoptosis, and cell adhesion. Thus, PTPN23 is probably involved in these processes, too.
- CHMP4B, charged multivesicular body protein 4B, a component of the endosomal sorting complex required for transport (ESCRT) complex III (ESCRT-III), which functions in the sorting of endocytosed cell-surface receptors into multivesicular endosomes. The interaction is mediated by BRO1 domain of PTPN23 [5].
- TSG101, Tumor susceptibility gene 101, a component of Endosomal Sorting Complex Required for Transport complex I (ESCRT-I). The main role of ESCRT-I is to recognize ubiquitinated cargo. The interaction is mediated by histidine domain of PTPN23 [5].
- Endophilin A1, an SH3 protein involved in receptor endocytosis. The interaction is mediated by histidine domain of PTPN23 [5].
- ALG-2, a protein important for apoptosis. The interaction is in a calcium-dependent manner [5].
- Grb2 and GrpL, two adapters of the Grb2 family which are essential for numerous signaling pathways. The interaction is mediated by histidine domain of PTPN23 [1].
- Rab4. PTPN23 interacts with Rab4 and regulates the spatial distribution of Rab4 and integrin trafficking in human and fruit fly, therefore modulating cell adhesion and migration [6].
- FAK, Focal Adhesion Kinase, a crucial regulator of cell migration. PTPN23 is a negative regulator of FAK phosphorylation, but it is unclear whether it dephosphorylates FAK in vivo [7].
PTPN23 and cancer
Suppression of PTPN23 increased E-cadherin internalization, impaired early endosome trafficking of E-cadherin, induced the expression of mesenchymal proteins, and caused cell scattering. The activity of SRC and beta-catenin was elevated when PTPN23 was suppressed. Thus, PTPN23 may increase the activity of SRC and the phosphorylation status of the E-cadherin/beta-catenin signaling complex to promote tumor growth and invasive behavior in breast cancer [3].
PTPN23 is a tumor suppressor in testicular germ cell tumors (TGCTs) [8].
PTPN23 is degraded by calpains in a calcium-dependent manner in T24 bladder carcinoma cells [9].
References
- Tanase CA. Histidine domain-protein tyrosine phosphatase interacts with Grb2 and GrpL. PLoS One. 2010 Dec 15;5(12):e14339. DOI:10.1371/journal.pone.0014339 |
- Gingras MC, Zhang YL, Kharitidi D, Barr AJ, Knapp S, Tremblay ML, and Pause A. HD-PTP is a catalytically inactive tyrosine phosphatase due to a conserved divergence in its phosphatase domain. PLoS One. 2009;4(4):e5105. DOI:10.1371/journal.pone.0005105 |
- Lin G, Aranda V, Muthuswamy SK, and Tonks NK. Identification of PTPN23 as a novel regulator of cell invasion in mammary epithelial cells from a loss-of-function screen of the 'PTP-ome'. Genes Dev. 2011 Jul 1;25(13):1412-25. DOI:10.1101/gad.2018911 |
- Mariotti M, Castiglioni S, Garcia-Manteiga JM, Beguinot L, and Maier JA. HD-PTP inhibits endothelial migration through its interaction with Src. Int J Biochem Cell Biol. 2009 Mar;41(3):687-93. DOI:10.1016/j.biocel.2008.08.005 |
- Ichioka F, Takaya E, Suzuki H, Kajigaya S, Buchman VL, Shibata H, and Maki M. HD-PTP and Alix share some membrane-traffic related proteins that interact with their Bro1 domains or proline-rich regions. Arch Biochem Biophys. 2007 Jan 15;457(2):142-9. DOI:10.1016/j.abb.2006.11.008 |
- Chen DY, Li MY, Wu SY, Lin YL, Tsai SP, Lai PL, Lin YT, Kuo JC, Meng TC, and Chen GC. The Bro1-domain-containing protein Myopic/HDPTP coordinates with Rab4 to regulate cell adhesion and migration. J Cell Sci. 2012 Oct 15;125(Pt 20):4841-52. DOI:10.1242/jcs.108597 |
- Castiglioni S, Maier JA, and Mariotti M. The tyrosine phosphatase HD-PTP: A novel player in endothelial migration. Biochem Biophys Res Commun. 2007 Dec 21;364(3):534-9. DOI:10.1016/j.bbrc.2007.10.022 |
- Tanaka K, Kondo K, Kitajima K, Muraoka M, Nozawa A, and Hara T. Tumor-suppressive function of protein-tyrosine phosphatase non-receptor type 23 in testicular germ cell tumors is lost upon overexpression of miR142-3p microRNA. J Biol Chem. 2013 Aug 16;288(33):23990-9. DOI:10.1074/jbc.M113.478891 |
- Castiglioni S and Maier JA. The tyrosine phosphatase HD-PTP (PTPN23) is degraded by calpains in a calcium-dependent manner. Biochem Biophys Res Commun. 2012 May 4;421(2):380-3. DOI:10.1016/j.bbrc.2012.04.024 |
Supplementary information
The position in this page is numbered by PTPN23 sequence below:
>HsapP079_AA symbol=PTPN23 CC1:CC1:PTP:PTPN23 [Homo sapiens] MRNRDSACAKDYASGWLGSLQLPAGRWHFSFPPVTSDFRHEGAGLGSWLSQQLQQLREWPGGRRVPAAMEAVPRMPMIWLDLKEAGDFHFQPAVKKFVLKNYGENPEAYNEELKKLELLRQNAVRVPRDFEGCSVLRKYLGQLHYLQSRVPMGSGQEAAVPVTWTEIFSGKSVAHEDIKYEQACILYNLGALHSMLGAMDKRVSEECAAGAFAYLREHFPQAYSVDMSRQILTLNVNLMLGQAQECLLEKSMLDNRKSFLVARISAQVVDYYKEACRALENPDTASLLGRIQKDWKKLVQMKIYYFAAVAHLHMGKQAEEQQKFGERVAYFQSALDKLNEAIKLAKGQPDTVQDALRFTMDVIGGKYNSAKKDNDFIYHEAVPALDTLQPVKGAPLVKPLPVNPTDPAVTGPDIFAKLVPMAAHEASSLYSEEKAKLLREMMAKIEDKNEVLDQFMDSMQLDPETVDNLDAYSHIPPQLMEKCAALSVRPDTVRNLVQSMQVLSGVFTDVEASLKDIRDLLEEDELLEQKFQEAVGQAGAISITSKAELAEVRREWAKYMEVHEKASFTNSELHRAMNLHVGNLRLLSGPLDQVRAALPTPALSPEDKAVLQNLKRILAKVQEMRDQRVSLEQQLRELIQKDDITASLVTTDHSEMKKLFEEQLKKYDQLKVYLEQNLAAQDRVLCALTEANVQYAAVRRVLSDLDQKWNSTLQTLVASYEAYEDLMKKSQEGRDFYADLESKVAALLERTQSTCQAREAARQQLLDRELKKKPPPRPTAPKPLLPRREESEAVEAGDPPEELRSLPPDMVAGPRLPDTFLGSATPLHFPPSPFPSSTGPGPHYLSGPLPPGTYSGPTQLIQPRAPGPHAMPVAPGPALYPAPAYTPELGLVPRSSPQHGVVSSPYVGVGPAPPVAGLPSAPPPQFSGPELAMAVRPATTTVDSIQAPIPSHTAPRPNPTPAPPPPCFPVPPPQPLPTPYTYPAGAKQPIPAQHHFSSGIPAGFPAPRIGPQPQPHPQPHPSQAFGPQPPQQPLPLQHPHLFPPQAPGLLPPQSPYPYAPQPGVLGQPPPPLHTQLYPGPAQDPLPAHSGALPFPSPGPPQPPHPPLAYGPAPSTRPMGPQAAPLTIRGPSSAGQSTPSPHLVPSPAPSPGPGPVPPRPPAAEPPPCLRRGAAAADLLSSSPESQHGGTQSPGGGQPLLQPTKVDAAEGRRPQALRLIERDPYEHPERLRQLQQELEAFRGQLGDVGALDTVWRELQDAQEHDARGRSIAIARCYSLKNRHQDVMPYDSNRVVLRSGKDDYINASCVEGLSPYCPPLVATQAPLPGTAADFWLMVHEQKVSVIVMLVSEAEMEKQKVARYFPTERGQPMVHGALSLALSSVRSTETHVERVLSLQFRDQSLKRSLVHLHFPTWPELGLPDSPSNLLRFIQEVHAHYLHQRPLHTPIIVHCSSGVGRTGAFALLYAAVQEVEAGNGIPELPQLVRRMRQQRKHMLQEKLHLRFCYEAVVRHVEQVLQRHGVPPPCKPLASASISQKNHLPQDSQDLVLGGDVPISSIQATIAKLSIRPPGGLESPVASLPGPAEPPGLPPASLPESTPIPSSSPPPLSSPLPEAPQPKEEPPVPEAPSSGPPSSSLELLASLTPEAFSLDSSLRGKQRMSKHNFLQAHNGQGLRATRPSDDPLSLLDPLWTLNKT
