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 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 test; meanwhile, the trees in different studies have different topologies as you can image [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. It is worthy pointing out that some of receptor PTP genes encodes isoforms without extracellular region and transmembrane region, which means they function as non-receptor PTPs.

  • PTPRA is a deuterostome-specific receptor PTP subfamily, which mainly function in tyrosine phosphorylation of cell signaling proteins. Human PTPRA (HEPTP/R-PTP-alpha) and PTPRE (R-PTP-EPSILON).
  • PTPRC (CD45) is a vertebrate-specific receptor PTP subfamily involved in lymphocyte activation. In particular, it dephosphorylates and activates Src kinases.
  • PTPRD (LAR) is a subfamily functions in nervous systems. Human has three members, PTPRF (LAR), PTPRD (RPTPdelta) and PTPRS (RPTPsigma), which can dephoshorylate different proteins mostly involved in cell signaling. The subfamily is not only found in animals but also single-cellular choanoflagellate.
  • PTPRG is an eumetazoan subfamily functions in nervous system and maybe cancer. Human has two members, PTPRG (R-PTP-GAMMA) and PTPRZ1 (RPTPbeta/R-PTP-zeta-2), which can interact with other PTPs, such as PTPRD.
  • PTPRK is a vertebrate subfamily that regulates cell-cell adhesion, implicated in human cancer and nervous system. Human has four members, PTPRK (LAR), PTPRM (PTP mu), PTPRT (RPTPrho), and PTPRU (PTP-RO/hPTP-J/PTP pi/PTP lambda).
  • PTPRB (R3) is a metazoan-specific subfamily functions in nervous system and immune systems. They have distinct substrates. One particular interesting example is that PTPRQ is lipid phosphatase rather than tyrosine phosphatase. Human has five members: PTPRB (VE-PTP), PTPRH (SAP-1), PTPRJ (CD148/DEP1/RPTP eta), PTPRO (GLEPP1/PTP phi), and PTPRQ.
  • PTPRN (IA-2) is a subfamily emerged in eumetazoan and duplicated in deuterostome. Human has two members, PTPRN (IA-2/ICA521) and PTPRN2 (phogrin), both of which are autoantigens of type I diabetes.
  • PTPN5 (STEP) is a tyrosine-specific subfamily. It is characterized by a kinase interaction motif (KIM), which is regulated by the phosphorylation state of a serine within the motif. PTPN5 emerged in eumetazoan and duplicated in vertebrates but absent from nematodes. Human has three members: PTPN5/STEP, PTPN7/HePTP, PTPRR/PTP-SL. 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. These evidences indicate they have unique functions different from each other.
  • Ptp69D is a subfamily similar to PTPRD. It involved in neuronal pathfinding. It emerged in metazoa but absent from vertebrates.
  • CG42327 is a subfamily found in arthropods. Its function is unclear.

Non-receptor PTPs

  • PTPN1 is a subfamily that dephoshorylates the kinases of various families. It emerged in animals and duplicated in vertebrates. Human has two members, PTPN1 (PTP1B) and PTPN2 (TCPTP).
  • PTPN3 is a non-receptor PTP subfamily 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/PTPH1 and PTPN4 have limited overlap.
  • PTPN6 (SHP) is a subfamily implicated in cancer and diabetes. It emerged in holozoa and duplicated in vertebrates. It is characterized by two 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 ecdysozoan. 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 ecdysozoan. PTPN13 has a single member in human: PTPN13/FAP-1/PTP1E/PTPL1/PTP-BAS.
  • 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.
  • PTPN20 is a vertebrate-specific subfamily involved in cytoskeleton organization.
  • 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.
  • CG7180 is a ecdysozoan-specific subfamily found in both nematodes and arthropods. Its function is unclear.
  • 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].

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]
All Medline abstracts: PubMed | HubMed
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