Phosphatase Subfamily PTPN14

Phosphatase Classification: Superfamily CC1: Family PTP: Subfamily PTPN14

Evolution

PTPRA is a metazoan-specific receptor PTP subfamily that is lost in all nematodes and duplicated in vertebrates, giving rise to PTPN14 (Pez) and PTPN21 (PTPD1, PTPRL10).

Domain Structure

All members have an N-terminal FERM/Band41 domain, a long middle region, and a C-terminal phosphatase domain. The FERM domain may mediate cytoskeletal association.

Functions

Drosophila Pez and human PTPN14 are associated with the hippo pathway. PTPN14 binds YAP through PPXY motifs and inhibits its transcription activation function [1]

Human PTPN21 physically associates with the Tec family kinases Tec and Bmx, using the middle region of PTPN21 and the PH domain of Tec and increases Tec kinase activity [2]. PTPN21 also binds and is phosphorylated by Src [3]. PTPN21 associates with the kinesins KIF1C [4] and KIF16B [5] and may be involved in vesicle transport between Golgi, ER and endosomes. PTPN21 also associates with FAK (focal adhesion kinase) and with actin, and is involved in cell motility and FAK autophosphorylation [6] and PTPN21 localizes along actin filaments and at adhesion plaques. PTPN21 can also complex with the PKA kinase and the AKAP121 mitochondrial anchoring protein. This binding redistributes PTPN21 from the cytoplasm to the outer mitochondrial membrane and can negatively regulate EGFR-Src signaling [7]

References

1. Huang JM, Nagatomo I, Suzuki E, Mizuno T, Kumagai T, Berezov A, Zhang H, Karlan B, Greene MI, and Wang Q. YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14. Oncogene. 2013 Apr 25;32(17):2220-9. DOI:10.1038/onc.2012.231 |
2. Jui HY, Tseng RJ, Wen X, Fang HI, Huang LM, Chen KY, Kung HJ, Ann DK, and Shih HM. Protein-tyrosine phosphatase D1, a potential regulator and effector for Tec family kinases. J Biol Chem. 2000 Dec 29;275(52):41124-32. DOI:10.1074/jbc.M007772200 |
3. Møller NP, Møller KB, Lammers R, Kharitonenkov A, Sures I, and Ullrich A. Src kinase associates with a member of a distinct subfamily of protein-tyrosine phosphatases containing an ezrin-like domain. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7477-81. DOI:10.1073/pnas.91.16.7477 |
4. Dorner C, Ciossek T, Müller S, Møller PH, Ullrich A, and Lammers R. Characterization of KIF1C, a new kinesin-like protein involved in vesicle transport from the Golgi apparatus to the endoplasmic reticulum. J Biol Chem. 1998 Aug 7;273(32):20267-75. DOI:10.1074/jbc.273.32.20267 |
5. Carlucci A, Porpora M, Garbi C, Galgani M, Santoriello M, Mascolo M, di Lorenzo D, Altieri V, Quarto M, Terracciano L, Gottesman ME, Insabato L, and Feliciello A. PTPD1 supports receptor stability and mitogenic signaling in bladder cancer cells. J Biol Chem. 2010 Dec 10;285(50):39260-70. DOI:10.1074/jbc.M110.174706 |
6. Carlucci A, Gedressi C, Lignitto L, Nezi L, Villa-Moruzzi E, Avvedimento EV, Gottesman M, Garbi C, and Feliciello A. Protein-tyrosine phosphatase PTPD1 regulates focal adhesion kinase autophosphorylation and cell migration. J Biol Chem. 2008 Apr 18;283(16):10919-29. DOI:10.1074/jbc.M707248200 |
7. Cardone L, Carlucci A, Affaitati A, Livigni A, DeCristofaro T, Garbi C, Varrone S, Ullrich A, Gottesman ME, Avvedimento EV, and Feliciello A. Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling. Mol Cell Biol. 2004 Jun;24(11):4613-26. DOI:10.1128/MCB.24.11.4613-4626.2004 |

PTPN14, PTPN21. Two copies in human, PTPN14 and PTPN21. Their substrates are beta-catenin, and BMX of Tec kinase family, respectively. The phosphatase is conserved from sponge to human and the kinase is conserved from Monosiga to human. The phosphatase and kinase lost together in C. elegans.