Phosphatase Family PTP

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Phosphatase Classification: Fold CC1: Superfamily CC1: Family PTP

The Protein Tyrosine Phosphatase Family (PTP) is the major tyrosine-specific family of phosphatases, present throughout animals and consisting of both transmembrane receptors (rPTPs) and non-receptor phosphatases (nrPTP), in several distinct subfamilies. This subfamily is known as High Molecular Weight Protein Tyrosine Phosphatase (HMWPTP) in the SCOP database. Compared to the related DSP and PTEN families, it has an extension to the beta-sheet of 3 antiparallel strands before strand 4.

Evolution

PTPs first emerged in holozoa. Among the 17 subfamilies present in human, 6 emerged in holozoa, 5 in metazoa, 3 in eumetazoa, and 3 in chordates or vertebrates. The relationship between the subfamilies is not well understood. The relationships between non-receptor PTPs and those between PTPRN and PTPRR/N5 and other subfamilies, as depicted by tree, are not significantly supported by statistical tests, and the branching order varies in published studies [1, 2, 3] (as well as PTP website at CSHL).

Subfamilies

The PTPs can be grouped into two classes: receptor PTPs and non-receptor PTPs.

Receptor PTPs

Receptor PTPs usually have an extracellular region, a single transmembrane region, and one or two intracytoplasmic catalytic phosphatase domains. Some receptor PTPs encode isoforms without extracellular or transmembrane regions, which function as non-receptor PTPs.

  • PTPRA is a deuterostome-specific subfamily. Human members are PTPRA (HEPTP/R-PTP-alpha) and PTPRE (R-PTP-EPSILON).
  • PTPRC (CD45) is a vertebrate-specific subfamily involved in lymphocyte activation. In particular, it dephosphorylates and activates Src kinases.
  • PTPRD (LAR) functions in the nervous system. The three human members, PTPRF (LAR), PTPRD (RPTPdelta) and PTPRS (RPTPsigma) dephosphorylate different proteins mostly involved in cell signaling. PTPRD is found in animals and choanoflagellates.
  • PTPRG is an eumetazoan subfamily that functions in nervous system and maybe cancer. Humans have two members, PTPRG (R-PTP-GAMMA) and PTPRZ1 (RPTPbeta/R-PTP-zeta-2/Rptpζ), which can interact with other PTPs, such as PTPRD.
  • PTPRK (R2B) is a chordate subfamily that regulates cell-cell adhesion, implicated in human cancer and the nervous system. The four human members are PTPRK (R-PTP-kappa), PTPRM (PTP mu), PTPRT (RPTPrho), and PTPRU (PTP-RO/hPTP-J/PTP pi/PTP lambda).
  • PTPRB (R3) is a metazoan-specific subfamily with functions in the nervous and immune systems. Human has five members: PTPRB (VE-PTP), PTPRH (SAP-1), PTPRJ (CD148/DEP1/RPTP eta), PTPRO (GLEPP1/PTP phi), and PTPRQ. They have distinct substrates. PTPRQ is lipid phosphatase rather than tyrosine phosphatase.
  • PTPRN (IA-2) is a metazoan family involved in neuronal and endocrine vesicle trafficking. No members have shown protein phosphatase activity, but at least one is reported to be a phospholipid phosphatase.
  • PTPRR (STEP) is a eumetazoan subfamily duplicated in vertebrates but absent from nematodes. . It is characterized by a kinase interaction motif (KIM), which is regulated by the phosphorylation state of a serine within the motif. Human has three members: PTPN5/STEP, PTPN7/HePTP, PTPRR/PTP-SL. Two of the three members have predicted transmembrane regions. They all regulate ERK pathway, but may have their specific substrates. They are expressed in different tissues, particularly, abundant in spleen, thymus, and different parts of brain.
  • Ptp69D is a subfamily similar to PTPRD. It is involved in neuronal pathfinding. It emerged in metazoa but is absent from vertebrates.
  • CG42327 is found in arthropods and probably other invertebrates. Its function is unclear.
  • NvecPTP-sf2 is found in cnidarians, and is of unknown function.
  • NvecPTP-sf6 is a Cnidarian-specific family most similar to PTPRD.


Non-receptor PTPs

  • PTPN1 dephosphorylates various families of kinases. It emerged in animals and duplicated in vertebrates. Human has two members, PTPN1 (PTP1B) and PTPN2 (TCPTP).
  • PTPN3 emerged in holozoa and duplicated in vertebrates. It has a domain combination of FERM domain, PEST sequence, PDZ domain and phosphatase domain. Human has two members of this subfamily, PTPN3 (PTPH1) and PTPN4 (PTPMEG). The expression pattern, substrates and interacting partners of PTPN3 and PTPN4 have limited overlap.
  • PTPN6 (SHP) is implicated in cancer and diabetes. It emerged in holozoa and duplicated in vertebrates. It is characterized by tandem SH2 domains.
  • PTPN9 is a metazoan subfamily functions in regulated secretory pathway. It has a characteristic accessory domain, a N-terminal Sec14p homology domain, which localizes it to secretory vesicles.
  • PTPN12 is a cytosolic PTP subfamily emerged in holozoan, duplicated in vertebrates and lost in ecdysozoa. It has a N-terminal phosphatase domain and a C-terminal region containing several proline-rich sequences. Human has three members, PTPN12/PTP-PEST, PTPN18/BDP and PTPN22/LYP. PTPN22/LYP variant R620W is associated with various autoimmune diseases, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D).
  • PTPN13 is a cytosolic PTP subfamily that has diverse functions. It has various substrates and interacting partners. PTPN13 has a FERM domain localizing it to plasma membrane, five PDZ domains interacting with different proteins, and a phosphatase domain. PTPN13 probably emerged in holozoan, but lost in various metazoan lineages such as ecdysozoa. PTPN13 has two human members: PTPN13/FAP-1/PTP1E/PTPL1/PTP-BAS, and PTPN20
  • PTPN14 (PEZ) is a cytoskeletal-associated phosphatase with roles in cell migration and adhesion, EGFR signaling and regulation of the Hippo pathway. PTPRN14 emerged in metazoa; it is lost in all nematodes and duplicated in vertebrates.
  • PTPN23 (HD-PTP) 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.
  • Ptp36E (CG7180) is a ecdysozoan-specific subfamily found in both nematodes and arthropods. Its function is unclear. Interestingly, it has two tandem PTP domains, which is a signature of receptor PTPs, and is similar to PTPRK, but lacks a transmembrane region or signal peptide.
  • Eak is a nematode-specific subfamily. C. elegans has two members eak-6 and sdf-9/eak-5 which potentiate AKT-1/PKB signaling. The function seems independent of phosphatase activity, because sdf-9 is predicted to be catalytically inactive given the replacement of cysteine by serine at the Cx5R motif.
  • Egg is a nematode-specific subfamily of pseudophosphatases. C. elegans has three members egg-3, egg-4, egg-5. Egg-4/egg-5 binds to the substrate-binding site of the kinase MBK-2 and inhibits the kinase to bind and phoshorylate its substrate, thereby inhibiting downstream signaling.
  • PtpB (a.k.a. PTP2 in Dictyostelium discoideum) is a subfamily found in most species in the order of Dictyosteliida (protein domain sequence identify >40%). In the species of Dictyostelium, it regulates MAP kinase ERK1 [4].
  • MbrePTP-sf1 is one of several clade-specific subfamilies that have no known functions.

Phosphatase Domain

The PTP phosphatase domain (PD) has ten motifs [1]. The motif 1 (nxxKNRY) is proposed to be pTr-recognition loop. The Y is substituted in i) D2 domain of human receptor PTPs, ii) catalytically inactive PTPs, including PTPRN, PTPN14, and PTPN23, iii) lipid phosphatases PTPRQ and PTPRN2.

Second phosphatase domain (D2)

PTPRC. D2 is necessary for PTPRC (CD45). The loss of D1 PTP activity after the deletion of all or even small portions of the D2 PTP domain [5, 6]. PTPRC (CD45) has a 19-aa acidic region in D2 domain, which serves as a regulatory module in lymphocyte activation [6].

PTPRA. The D2 of PTPRA demonstrated higher susceptibility to oxidation [7]. The oxidation at the cysteine of Cx5R catalytic motif led to inactivation in PTPN1 (PTP1B).

Minor subfamilies

Several species-specific subfamilies are seen:


References

  1. Andersen JN, Mortensen OH, Peters GH, Drake PG, Iversen LF, Olsen OH, Jansen PG, Andersen HS, Tonks NK, and Møller NP. Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol Cell Biol. 2001 Nov;21(21):7117-36. DOI:10.1128/MCB.21.21.7117-7136.2001 | PubMed ID:11585896 | HubMed [Andersen01]
  2. Andersen JN, Jansen PG, Echwald SM, Mortensen OH, Fukada T, Del Vecchio R, Tonks NK, and Møller NP. A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. FASEB J. 2004 Jan;18(1):8-30. DOI:10.1096/fj.02-1212rev | PubMed ID:14718383 | HubMed [Andersen04]
  3. Barr AJ, Ugochukwu E, Lee WH, King ON, Filippakopoulos P, Alfano I, Savitsky P, Burgess-Brown NA, Müller S, and Knapp S. Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell. 2009 Jan 23;136(2):352-63. DOI:10.1016/j.cell.2008.11.038 | PubMed ID:19167335 | HubMed [Barr09]
  4. Sun T and Kim L. Tyrosine phosphorylation-mediated signaling pathways in dictyostelium. J Signal Transduct. 2011;2011:894351. DOI:10.1155/2011/894351 | PubMed ID:21776390 | HubMed [Sun11]
  5. Ng DH, Maiti A, and Johnson P. Point mutation in the second phosphatase domain of CD45 abrogates tyrosine phosphatase activity. Biochem Biophys Res Commun. 1995 Jan 5;206(1):302-9. DOI:10.1006/bbrc.1995.1042 | PubMed ID:7818534 | HubMed [Ng95]
  6. Wang Y, Liang L, and Esselman WJ. Regulation of the calcium/NF-AT T cell activation pathway by the D2 domain of CD45. J Immunol. 2000 Mar 1;164(5):2557-64. PubMed ID:10679094 | HubMed [Wang00]
  7. Persson C, Sjöblom T, Groen A, Kappert K, Engström U, Hellman U, Heldin CH, den Hertog J, and Ostman A. Preferential oxidation of the second phosphatase domain of receptor-like PTP-alpha revealed by an antibody against oxidized protein tyrosine phosphatases. Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1886-91. DOI:10.1073/pnas.0304403101 | PubMed ID:14762163 | HubMed [Persson04]
All Medline abstracts: PubMed | HubMed