Phosphatase Subfamily PTPN14

Phosphatase Classification: Superfamily CC1: Family PTP: Subfamily PTPN14

PTPN14 is a cytoskeleton-associated phosphatase involved in cell migration and adhesion, EGFR signaling and regulation of the Hippo pathway.

Evolution

PTPN14 is a metazoan-specific receptor PTP subfamily that is lost in all nematodes and duplicated in vertebrates, giving rise to PTPN14 (Pez, PTPD2, PTP36) and PTPN21 (PTPD1, PTPRL10).

Domains

All members have an N-terminal FERM/Band4.1 domain, a long middle region, and a C-terminal phosphatase domain. The middle region contains a conserved PPxY motif (PPPY) that interacts with WW domains (567-570 in human PTPN14), and other motifs that are conserved in most vertebrate and invertebrate members (see technical note). The FERM domain may mediate cytoskeletal association.

Functions

Human PTPN14 and Drosophila Pez are negative regulators of the hippo pathway. PTPN14 binds the WW domain of YAP through its PPXY motif, sequestering it in the cytoplasm and inhibiting its transcriptional regulatory function [1, 2]. PTPN14 also binds the Hippo pathway protein Kibra though it's WW domain. This complex can activate the LATS1 kinase, independent of MST kinases [3], also resulting in cytoplasmic sequestration of YAP. Drosophila Pez also binds Kibra and antagonizes Yorkie/YAP function in the midgut epithelium [4].

PTPN14 has been genetically associated with hereditary haemorrhagic telangiectasia, a vascular disease also associated with TGFb signaling and cell migration [5].

PTPN14 mutations have been seen in several cancer types [6]. In colorectal cell lines, PTPN14 was shown to dephosphorylate p130Cas on Y128, a Src phosphorylation site [6]. PTPN14 can also act on beta-catenin at adherens junctions [7].

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 [8]. Both Tec and PTPN14 are co-lost in all nematode species. PTPN21 also binds and is phosphorylated by Src [9].

PTPN21 associates with the kinesins KIF1C [10] and KIF16B [11] 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 [12] 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 [13]. PTPN14 can also translocate to the nucleus in proliferating cells [14].

PTPN21 substitutes a glutamate for the catalytic aspartate in the WPD loop, and this structurally appears to reduce or block catalytic activity, while still retaining substate binding [15].

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. Liu X, Yang N, Figel SA, Wilson KE, Morrison CD, Gelman IH, and Zhang J. PTPN14 interacts with and negatively regulates the oncogenic function of YAP. Oncogene. 2013 Mar 7;32(10):1266-73. DOI:10.1038/onc.2012.147 |
3. Wilson KE, Li YW, Yang N, Shen H, Orillion AR, and Zhang J. PTPN14 forms a complex with Kibra and LATS1 proteins and negatively regulates the YAP oncogenic function. J Biol Chem. 2014 Aug 22;289(34):23693-700. DOI:10.1074/jbc.M113.534701 |
4. Poernbacher I, Baumgartner R, Marada SK, Edwards K, and Stocker H. Drosophila Pez acts in Hippo signaling to restrict intestinal stem cell proliferation. Curr Biol. 2012 Mar 6;22(5):389-96. DOI:10.1016/j.cub.2012.01.019 |
5. Benzinou M, Clermont FF, Letteboer TG, Kim JH, Espejel S, Harradine KA, Arbelaez J, Luu MT, Roy R, Quigley D, Higgins MN, Zaid M, Aouizerat BE, van Amstel JK, Giraud S, Dupuis-Girod S, Lesca G, Plauchu H, Hughes CC, Westermann CJ, and Akhurst RJ. Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. Nat Commun. 2012 Jan 10;3:616. DOI:10.1038/ncomms1633 |
6. Zhang P, Guo A, Possemato A, Wang C, Beard L, Carlin C, Markowitz SD, Polakiewicz RD, and Wang Z. Identification and functional characterization of p130Cas as a substrate of protein tyrosine phosphatase nonreceptor 14. Oncogene. 2013 Apr 18;32(16):2087-95. DOI:10.1038/onc.2012.220 |
7. Wadham C, Gamble JR, Vadas MA, and Khew-Goodall Y. The protein tyrosine phosphatase Pez is a major phosphatase of adherens junctions and dephosphorylates beta-catenin. Mol Biol Cell. 2003 Jun;14(6):2520-9. DOI:10.1091/mbc.e02-09-0577 |
8. 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 |
9. 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 |
10. 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 |
11. 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 |
12. 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 |
13. 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 |
14. Wadham C, Gamble JR, Vadas MA, and Khew-Goodall Y. Translocation of protein tyrosine phosphatase Pez/PTPD2/PTP36 to the nucleus is associated with induction of cell proliferation. J Cell Sci. 2000 Sep;113 ( Pt 17):3117-23. DOI:10.1242/jcs.113.17.3117 |
15. Chen KE, Li MY, Chou CC, Ho MR, Chen GC, Meng TC, and Wang AH. Substrate specificity and plasticity of FERM-containing protein tyrosine phosphatases. Structure. 2015 Apr 7;23(4):653-64. DOI:10.1016/j.str.2015.01.017 |