Difference between revisions of "Phosphatase Subfamily PTPN23"

Revision as of 22:23, 7 September 2016

Phosphatase Classification: Fold CC1: Superfamily CC1: Family PTP: Subfamily PTPN23 (HD-PTP)

PTPN23 subfamily functions in endosomal protein sorting. It has a signature BRO1 domain that distinguishes it from other protein phosphatases. It is under debate whether PTPN23 is catalytically inactive. PTPN23 emerged in holozoan but absent from some individual lineages, such as sponge and nematode.

Evolution

PTPN23 is found across holozoa. Nematodes have a protein (ego-2/Y53H1C in C. elegans) that retains the BRO1 and ALIX_LYPXL_bnd domains but has lost the phosphatase domain. Fungi also have a BRO1-ALIX_LYPXL_bnd protein (e.g. S. cerevisiae Bro1)

Domain Structure

PTPN23 has an N-terminal BRO1 domain not seen in other protein phosphatases. The BRO1 domain of fungal and mammalian proteins binds with multivesicular body components (ESCRT-III proteins) such as yeast Snf7 and mammalian CHMP4b, and can function to 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 [1] and Figure 2 [2]. The accessory domains mediates the interactions with different protein (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 [3].

PTPN23 associates with the SMN complex involved in RNA splicing [4]

Is PTPN23 catalytically inactive?

PTPN23 was reported to be catalytically inactive, with no phosphatase activity toward tyrosine or lipids [5]. 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 [5]. 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 [6], while another showed that PTPN23 did not modulate the levels of Src phosphorylation either in vitro and in vivo [7].

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. In fact, PTPN23 is a key regulator of endocytic trafficking in which ESCRT-III binding is important but not strictly essential [8]. 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 [2].

• 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 [2, 9].

• 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 [2]).

• UBAP1, ubiquitin-associated protein 1, a ESCRT-I component. The interaction is mediated by PTPN23 V-domain with coiled-coil motifs [10].

• 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 [9].

• Endophilin A1, an SH3 protein involved in receptor endocytosis. The interaction is mediated by histidine domain of PTPN23 [9].

• ALG-2, a protein important for apoptosis. The interaction is in a calcium-dependent manner [9].

• 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 [11].

• 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 [12].

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 [6].

PTPN23 is a tumor suppressor in testicular germ cell tumors (TGCTs) [13].

PTPN23 is degraded by calpains in a calcium-dependent manner in T24 bladder carcinoma cells [14].

References

1. Error fetching PMID 21179510: [Tanase10]
2. Error fetching PMID 23477725: [Ali13]
3. Error fetching PMID 16720300: [Mariotti06]
4. Error fetching PMID 25392300: [Husedzinovic]
5. Error fetching PMID 19340315: [Gingras09]
6. Error fetching PMID 21724833: [Lin11]
7. Error fetching PMID 18762272: [Mariotti09]
8. Error fetching PMID 18434552: [Doyotte08]
9. Error fetching PMID 17174262: [Ichioka07]
10. Error fetching PMID 21757351: [Stefani11]
11. Error fetching PMID 22825871: [Chen12]
12. Error fetching PMID 17959146: [Castiglioni07]
13. Error fetching PMID 23843459: [Tanaka13]
14. Error fetching PMID 22510412: [Castiglioni12]

Supplementary information

The position in this page is numbered by PTPN23 sequence below:

>HsapP079_AA symbol=PTPN23 CC1:CC1:PTP:PTPN23 [Homo sapiens] MRNRDSACAKDYASGWLGSLQLPAGRWHFSFPPVTSDFRHEGAGLGSWLSQQLQQLREWPGGRRVPAAMEAVPRMPMIWLDLKEAGDFHFQPAVKKFVLKNYGENPEAYNEELKKLELLRQNAVRVPRDFEGCSVLRKYLGQLHYLQSRVPMGSGQEAAVPVTWTEIFSGKSVAHEDIKYEQACILYNLGALHSMLGAMDKRVSEECAAGAFAYLREHFPQAYSVDMSRQILTLNVNLMLGQAQECLLEKSMLDNRKSFLVARISAQVVDYYKEACRALENPDTASLLGRIQKDWKKLVQMKIYYFAAVAHLHMGKQAEEQQKFGERVAYFQSALDKLNEAIKLAKGQPDTVQDALRFTMDVIGGKYNSAKKDNDFIYHEAVPALDTLQPVKGAPLVKPLPVNPTDPAVTGPDIFAKLVPMAAHEASSLYSEEKAKLLREMMAKIEDKNEVLDQFMDSMQLDPETVDNLDAYSHIPPQLMEKCAALSVRPDTVRNLVQSMQVLSGVFTDVEASLKDIRDLLEEDELLEQKFQEAVGQAGAISITSKAELAEVRREWAKYMEVHEKASFTNSELHRAMNLHVGNLRLLSGPLDQVRAALPTPALSPEDKAVLQNLKRILAKVQEMRDQRVSLEQQLRELIQKDDITASLVTTDHSEMKKLFEEQLKKYDQLKVYLEQNLAAQDRVLCALTEANVQYAAVRRVLSDLDQKWNSTLQTLVASYEAYEDLMKKSQEGRDFYADLESKVAALLERTQSTCQAREAARQQLLDRELKKKPPPRPTAPKPLLPRREESEAVEAGDPPEELRSLPPDMVAGPRLPDTFLGSATPLHFPPSPFPSSTGPGPHYLSGPLPPGTYSGPTQLIQPRAPGPHAMPVAPGPALYPAPAYTPELGLVPRSSPQHGVVSSPYVGVGPAPPVAGLPSAPPPQFSGPELAMAVRPATTTVDSIQAPIPSHTAPRPNPTPAPPPPCFPVPPPQPLPTPYTYPAGAKQPIPAQHHFSSGIPAGFPAPRIGPQPQPHPQPHPSQAFGPQPPQQPLPLQHPHLFPPQAPGLLPPQSPYPYAPQPGVLGQPPPPLHTQLYPGPAQDPLPAHSGALPFPSPGPPQPPHPPLAYGPAPSTRPMGPQAAPLTIRGPSSAGQSTPSPHLVPSPAPSPGPGPVPPRPPAAEPPPCLRRGAAAADLLSSSPESQHGGTQSPGGGQPLLQPTKVDAAEGRRPQALRLIERDPYEHPERLRQLQQELEAFRGQLGDVGALDTVWRELQDAQEHDARGRSIAIARCYSLKNRHQDVMPYDSNRVVLRSGKDDYINASCVEGLSPYCPPLVATQAPLPGTAADFWLMVHEQKVSVIVMLVSEAEMEKQKVARYFPTERGQPMVHGALSLALSSVRSTETHVERVLSLQFRDQSLKRSLVHLHFPTWPELGLPDSPSNLLRFIQEVHAHYLHQRPLHTPIIVHCSSGVGRTGAFALLYAAVQEVEAGNGIPELPQLVRRMRQQRKHMLQEKLHLRFCYEAVVRHVEQVLQRHGVPPPCKPLASASISQKNHLPQDSQDLVLGGDVPISSIQATIAKLSIRPPGGLESPVASLPGPAEPPGLPPASLPESTPIPSSSPPPLSSPLPEAPQPKEEPPVPEAPSSGPPSSSLELLASLTPEAFSLDSSLRGKQRMSKHNFLQAHNGQGLRATRPSDDPLSLLDPLWTLNKT