Phosphatase Subfamily PTPN23

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 subfamily is found across metazoan except nematode. Evidenced by BRO1 domain unique in PTPN23 among all protein phosphatases, PTPN23 is also found in unicellular choanoflagellates. Thus, PTPN23 probably emerged in holozoan.

Domain

PTPN23 has a characterized BRO1 domain that distinguishes it from other PTPs and even all 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).

Besides its N-terminal BRO1 domain, PTPN23 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 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 also known as Histidine Domain-Protein Tyrosine Phosphatase (HD-PTP), is a multidomain cytosolic member of the Bro1-domain-containing protein family. It is widely expressed in different tissues (see GTEx). Fibroblast Growth Factor-2 induces PTPN23 degradation via the proteasome system, While Vascular Endothelial Growth Factor does not affect protein levels [3].

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 [4].

However, another study found SRC, E-cadherin, and beta-catenin are direct substrates of PTPN23 [5]. But, yet another study showed that PTPN23 did not modulate the levels of Src phosphorylation both in vitro and in vivo [6].

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 [7]. 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, 8].

• 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 [9].

• 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 [8].

• Endophilin A1, an SH3 protein involved in receptor endocytosis. The interaction is mediated by histidine domain of PTPN23 [8].

• ALG-2, a protein important for apoptosis. The interaction is in a calcium-dependent manner [8].

• 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 [10].

• 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 [11].

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 [5].

PTPN23 is a tumor suppressor in testicular germ cell tumors (TGCTs) [12].

PTPN23 is degraded by calpains in a calcium-dependent manner in T24 bladder carcinoma cells [13].

References

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Supplementary information

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

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