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_Subfamily_PTPN23|Subfamily PTPN23]] (HD-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) | ||
| − | PTPN23 | + | PTPN23 functions in endosomal protein sorting. It has a signature BRO1 domain that distinguishes it from other protein phosphatases. It is unclear whether PTPN23 is catalytically inactive. PTPN23 emerged in holozoa but absent from some lineages, such as sponge and nematodes. |
===Evolution=== | ===Evolution=== | ||
| − | PTPN23 is found across [[holozoa]]. | + | PTPN23 is found across [[holozoa]]. <cite>Chen</cite>. A nematode ortholog (ego-2/Y53H1C in C. elegans) retains the BRO1 and ALIX_LYPXL_bnd domains but has lost the phosphatase domain. Fungi also have a likely ortholog (Bro1 in S. cerevisiae) that lacks a phosphatase domain, but retains the BRO1 and ALIX_LYPXL_bnd domains. |
===Domain Structure === | ===Domain Structure === | ||
| − | PTPN23 has an N-terminal BRO1 domain not seen in other protein phosphatases. | + | PTPN23 has an N-terminal BRO1 domain not seen in other protein phosphatases. Fungal and mammalian BRO1 domains bind multivesicular body components (ESCRT-III proteins) such as yeast Snf7 and mammalian CHMP4b, and can target BRO1 domain-containing proteins to endosomes (see [http://www.ebi.ac.uk/interpro/entry/IPR004328 InterPro]). |
| − | PTPN23 has five other main regions: | + | PTPN23 has five other main regions: an ALIX_LYPXL_bnd domain immediately after the BRO1 domain, a central proline-rich domain with numerous dispersed His residues (HD), a phosphatase domain (PTP) 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> and Figure 2 <cite>Ali13</cite>. The accessory domains mediates the interactions with different proteins (see below). |
===Functions=== | ===Functions=== | ||
| − | PTPN23 is widely expressed in different tissues (see [http://www.gtexportal.org/home/gene/PTPN23 GTEx]). Fibroblast Growth Factor-2 induces PTPN23 degradation via the proteasome, while | + | PTPN23 is widely expressed in different tissues (see [http://www.gtexportal.org/home/gene/PTPN23 GTEx]). Fibroblast Growth Factor-2 induces PTPN23 degradation via the proteasome, while VEGF did not <cite>Mariotti06</cite>. |
| + | |||
| + | PTPN23 associates with the SMN complex involved in RNA splicing <cite>Husedzinovic</cite> | ||
====== Is PTPN23 catalytically inactive? ====== | ====== Is PTPN23 catalytically inactive? ====== | ||
| − | PTPN23 was reported to be catalytically inactive, | + | PTPN23 was reported to be catalytically inactive, with no phosphatase activity toward tyrosine or lipids <cite>Gingras09</cite>. 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, induced tyrosine phosphatase activity <cite>Gingras09</cite>. The serine is conserved in all vertebrate PTPN23; some invertebrate PTPN23 have alanine in this position (e.g. Monosiga, Nematostella and sea urchin), and others have other residues that may or may not be catalytically active. |
| − | + | Other studies have disagreed on catalytic activity: one claimed that Src, E-cadherin, and beta-catenin are direct substrates of PTPN23 <cite>Lin11</cite>, while another showed that PTPN23 did not modulate the levels of Src phosphorylation either in vitro and in vivo <cite>Mariotti09</cite>. | |
====== Interacting partners ====== | ====== Interacting partners ====== | ||
| − | PTPN23 has | + | PTPN23 has several interacting partners, which function in endosomal protein sorting and trafficking, apoptosis, and cell adhesion. PTPN23 is a known regulator of endocytic trafficking in which ESCRT-III binding is important but not strictly essential <cite>Doyotte08</cite>. PTPN23 also acts as a central coordinator of the ESCRT pathway for EGFR, where concerted recruitment of CHMP4B and UBPY to PTPN23 and the engagement of UBPY/USP8 by STAM2 displaces ESCRT-0 from PTPN23, deubiquitinates EGFR, and releases ESCRT-0 from cargo in favor of ESCRT-III <cite>Ali13</cite>. |
* [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, Ali13</cite>. | * [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, Ali13</cite>. | ||
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* 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>. | * 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>. | ||
| − | * 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>. | + | * 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 ====== | ====== PTPN23 and cancer ====== | ||
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#Castiglioni12 pmid=22510412 | #Castiglioni12 pmid=22510412 | ||
#Chen12 pmid=22825871 | #Chen12 pmid=22825871 | ||
| + | #Chen pmid=28400531 | ||
#Doyotte08 pmid=18434552 | #Doyotte08 pmid=18434552 | ||
#Ichioka07 pmid=17174262 | #Ichioka07 pmid=17174262 | ||
#Gingras09 pmid=19340315 | #Gingras09 pmid=19340315 | ||
| + | #Husedzinovic pmid=25392300 | ||
#Lin11 pmid=21724833 | #Lin11 pmid=21724833 | ||
#Mariotti06 pmid=16720300 | #Mariotti06 pmid=16720300 | ||
Latest revision as of 07:59, 24 July 2017
Phosphatase Classification: Fold CC1: Superfamily CC1: Family PTP: Subfamily PTPN23 (HD-PTP)
PTPN23 functions in endosomal protein sorting. It has a signature BRO1 domain that distinguishes it from other protein phosphatases. It is unclear whether PTPN23 is catalytically inactive. PTPN23 emerged in holozoa but absent from some lineages, such as sponge and nematodes.
Evolution
PTPN23 is found across holozoa. [1]. A nematode ortholog (ego-2/Y53H1C in C. elegans) retains the BRO1 and ALIX_LYPXL_bnd domains but has lost the phosphatase domain. Fungi also have a likely ortholog (Bro1 in S. cerevisiae) that lacks a phosphatase domain, but retains the BRO1 and ALIX_LYPXL_bnd domains.
Domain Structure
PTPN23 has an N-terminal BRO1 domain not seen in other protein phosphatases. Fungal and mammalian BRO1 domains bind multivesicular body components (ESCRT-III proteins) such as yeast Snf7 and mammalian CHMP4b, and can target BRO1 domain-containing proteins to endosomes (see InterPro).
PTPN23 has five other main regions: an ALIX_LYPXL_bnd domain immediately after the BRO1 domain, a central proline-rich domain with numerous dispersed His residues (HD), a phosphatase domain (PTP) 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 [2] and Figure 2 [3]. The accessory domains mediates the interactions with different proteins (see below).
Functions
PTPN23 is widely expressed in different tissues (see GTEx). Fibroblast Growth Factor-2 induces PTPN23 degradation via the proteasome, while VEGF did not [4].
PTPN23 associates with the SMN complex involved in RNA splicing [5]
Is PTPN23 catalytically inactive?
PTPN23 was reported to be catalytically inactive, with no phosphatase activity toward tyrosine or lipids [6]. 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, induced tyrosine phosphatase activity [6]. The serine is conserved in all vertebrate PTPN23; some invertebrate PTPN23 have alanine in this position (e.g. Monosiga, Nematostella and sea urchin), and others have other residues that may or may not be catalytically active.
Other studies have disagreed on catalytic activity: one claimed that Src, E-cadherin, and beta-catenin are direct substrates of PTPN23 [7], while another showed that PTPN23 did not modulate the levels of Src phosphorylation either in vitro and in vivo [8].
Interacting partners
PTPN23 has several interacting partners, which function in endosomal protein sorting and trafficking, apoptosis, and cell adhesion. PTPN23 is a known regulator of endocytic trafficking in which ESCRT-III binding is important but not strictly essential [9]. PTPN23 also acts as a central coordinator of the ESCRT pathway for EGFR, where concerted recruitment of CHMP4B and UBPY to PTPN23 and the engagement of UBPY/USP8 by STAM2 displaces ESCRT-0 from PTPN23, deubiquitinates EGFR, and releases ESCRT-0 from cargo in favor of ESCRT-III [3].
- 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 [3, 10].
- STAM2, Signal transducing adapter molecule 2. The interaction is mediated by two sites: PTPN23 BRO1 domain and STAM2 core domain, PTPN23 HD domain and STAM SH3 domain (see Figure 2 in [3]).
- UBAP1, ubiquitin-associated protein 1, a ESCRT-I component. The interaction is mediated by PTPN23 V-domain with coiled-coil motifs [11].
- 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 [10].
- Endophilin A1, an SH3 protein involved in receptor endocytosis. The interaction is mediated by histidine domain of PTPN23 [10].
- ALG-2, a protein important for apoptosis. The interaction is in a calcium-dependent manner [10].
- 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 [2].
- 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 [12].
- 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 [13].
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 [7].
PTPN23 is a tumor suppressor in testicular germ cell tumors (TGCTs) [14].
PTPN23 is degraded by calpains in a calcium-dependent manner in T24 bladder carcinoma cells [15].
References
- Chen MJ, Dixon JE, and Manning G. Genomics and evolution of protein phosphatases. Sci Signal. 2017 Apr 11;10(474). DOI:10.1126/scisignal.aag1796 |
- 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 |
- Ali N, Zhang L, Taylor S, Mironov A, Urbé S, and Woodman P. Recruitment of UBPY and ESCRT exchange drive HD-PTP-dependent sorting of EGFR to the MVB. Curr Biol. 2013 Mar 18;23(6):453-61. DOI:10.1016/j.cub.2013.02.033 |
- Mariotti M, Castiglioni S, Beguinot L, and Maier JA. The tyrosine phosphatase HD-PTP is regulated by FGF-2 through proteasome degradation. Front Biosci. 2006 Sep 1;11:2138-43. DOI:10.2741/1956 |
- Husedzinovic A, Neumann B, Reymann J, Draeger-Meurer S, Chari A, Erfle H, Fischer U, and Gruss OJ. The catalytically inactive tyrosine phosphatase HD-PTP/PTPN23 is a novel regulator of SMN complex localization. Mol Biol Cell. 2015 Jan 15;26(2):161-71. DOI:10.1091/mbc.E14-06-1151 |
- 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 |
- Doyotte A, Mironov A, McKenzie E, and Woodman P. The Bro1-related protein HD-PTP/PTPN23 is required for endosomal cargo sorting and multivesicular body morphogenesis. Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6308-13. DOI:10.1073/pnas.0707601105 |
- 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 |
- Stefani F, Zhang L, Taylor S, Donovan J, Rollinson S, Doyotte A, Brownhill K, Bennion J, Pickering-Brown S, and Woodman P. UBAP1 is a component of an endosome-specific ESCRT-I complex that is essential for MVB sorting. Curr Biol. 2011 Jul 26;21(14):1245-50. DOI:10.1016/j.cub.2011.06.028 |
- 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
