Phosphatase Family PTP

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.

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 (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 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.

Below are non-receptor PTP subfamilies:

• PTPN1

• PTPN3

• PTPN6

• PTPN9 The N9 subfamily consists of one gene in humans (PTPN9/PTP-MEG2), and homologs throughout metazoans. The protein has a Sec14 domain N-teminal of the PTP domain, which targets the protein to the membrane of secretory vesicles (PMID: 15322554), where it regulates vesicle fusion. PTPN9 desphosphorylates and activates NSF (N-ethylmaleimide-sensitive factor), a regulator of vesicle fusion. The human gene is also implicated in signaling between insulin receptor (InsR) and the FoxO transcription factor (PMID: 16679294).

• PTPN12 Three copies in human, PTPN12, PTPN18 and PTPN22. They have a phosphatase domain and C-terminal PEST motif involved in protein degradation. PTPN12 has various substrates, including tyrosine kinases cABL of Abl kinase family and PYK2 of FAK kinase family. PTPN18 can dephoshorylate ErbB2 of EGFR kinase family. The N12 subfamily is found from Monosiga to human, as is the Abl kinase family. The other two kinase families FAK and EGFR are conserved from sponge to human.

• PTPN13 PTPN13. Single copy in each organism. It has FERM and multiple PDZ domains in addition to phosphatase domain. It is conserved from Monosiga to human but lost in sponge, C. elegans and fly. Mice homozygous for its null allele exhibit abnormal T-helper cell differentiation. Its presence in Monosiga and absence is various organisms suggests its basal but non-essential function.

• PTPN14 PTPN14 is a cytoskeletal-associated phosphatase with roles in cell migration and adhesion, EGFR signaling and regulation of the Hippo pathway.

• PTPN20 PTPN20. It is vertebrate specific. It has two copies in human, PTPN20A and PTPN20B. Their sequences are almost identical. Their function is unclear.

• 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.

• Ptp69D A metazoan RPTP family similar to PTPRD, involved in neuronal pathfinding, but absent from vertebrates.