Phosphatase Subfamily PTPN1

Phosphatase Classification: Fold CC1:Superfamily CC1: Family PTP: Subfamily PTPN1

The PTPN1 subfamily dephoshorylates kinases of various families, including Insulin receptor kinase (InsR), epidermal growth factor receptor kinase (EGFR), JAK (JAK2 and TYK2).

Evolution

PTPN1 subfamily emerged in animals, as it is found in most if not all eumetazoa, Porifera (e.g. sponge) and Placozoa (e.g. Trichoplax), but absent from Choanoflagellata (e.g. Monosiga) (for the phylogeny of animal at here). In human, there are two copies: PTPN1 (PTP1B) and PTPN2 (TCPTP). The two copies can be traced back to the time when vertebrates emerged. The orthologs for each of them are found in most vertebrates from fish to primates, and there is a single copy in non-vertebrate metazoa.

Domain

The PTPN1 subfamily has a single structural domain, phosphatase domain.

Functions

The PTPN1 subfamily has various functions [1, 2, 3, 4]. It dephoshorylates kinases of various families, such as Insulin receptor kinase (InsR), epidermal growth factor receptor kinase (EGFR), JAK (JAK2 and TYK2):

Human PTPN1 (PTPB1)

Substrates

• BRK. PTPN1 (PTP1B) inhibited BRK, a member of SRM subfamily, SRC family, by directly dephosphorylating the Tyr-342 autophosphorylation site [5].

Other functions and regulatory mechanisms

• Human PTPN1 (PTPB1) is regulated via glutathionylation of cysteine at the catalytic motif Cx5R [6].
• Human PTPN1 (PTPB1) plays a key role in regulating dendritic cell maturation, migration and T cell activation [7].
• Humant PTPN1 (PTB1) is involved in the regulation of blood brain barrier endothelial permeability [8].

Human PTPN2

Substrates

• STAT3. PTPN2 (TCPTP) interacts with, dephosphorylates and inactivates STAT3. The activity is enhanced by STAT3-Interacting Protein As a Repressor (SIPAR) [9].

References

1. Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, Kim YB, Elmquist JK, Tartaglia LA, Kahn BB, and Neel BG. PTP1B regulates leptin signal transduction in vivo. Dev Cell. 2002 Apr;2(4):489-95. DOI:10.1016/s1534-5807(02)00148-x |
2. Tonks NK. PTP1B: from the sidelines to the front lines!. FEBS Lett. 2003 Jul 3;546(1):140-8. DOI:10.1016/s0014-5793(03)00603-3 |
3. Zhang S and Zhang ZY. PTP1B as a drug target: recent developments in PTP1B inhibitor discovery. Drug Discov Today. 2007 May;12(9-10):373-81. DOI:10.1016/j.drudis.2007.03.011 |
4. Tiganis T. PTP1B and TCPTP--nonredundant phosphatases in insulin signaling and glucose homeostasis. FEBS J. 2013 Jan;280(2):445-58. DOI:10.1111/j.1742-4658.2012.08563.x |
5. Fan G, Aleem S, Yang M, Miller WT, and Tonks NK. Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase. J Biol Chem. 2015 Jun 26;290(26):15934-47. DOI:10.1074/jbc.M115.651703 |
6. Barrett WC, DeGnore JP, König S, Fales HM, Keng YF, Zhang ZY, Yim MB, and Chock PB. Regulation of PTP1B via glutathionylation of the active site cysteine 215. Biochemistry. 1999 May 18;38(20):6699-705. DOI:10.1021/bi990240v |
7. Martin-Granados C, Prescott AR, Le Sommer S, Klaska IP, Yu T, Muckersie E, Giuraniuc CV, Grant L, Delibegovic M, and Forrester JV. A key role for PTP1B in dendritic cell maturation, migration, and T cell activation. J Mol Cell Biol. 2015 Dec;7(6):517-28. DOI:10.1093/jmcb/mjv032 |
8. Siddiqui MR, Mayanil CS, Kim KS, and Tomita T. Angiopoietin-1 Regulates Brain Endothelial Permeability through PTPN-2 Mediated Tyrosine Dephosphorylation of Occludin. PLoS One. 2015;10(6):e0130857. DOI:10.1371/journal.pone.0130857 |
9. Ren F, Geng Y, Minami T, Qiu Y, Feng Y, Liu C, Zhao J, Wang Y, Fan X, Wang Y, Li M, Li J, and Chang Z. Nuclear termination of STAT3 signaling through SIPAR (STAT3-Interacting Protein As a Repressor)-dependent recruitment of T cell tyrosine phosphatase TC-PTP. FEBS Lett. 2015 Jul 8;589(15):1890-6. DOI:10.1016/j.febslet.2015.05.031 |