PTPN14 (protein tyrosine phosphatase, non-receptor type 14)

2013-01-01   Nicholas Hauschild , Leila Belle , Yeesim Khew-Goodall 

Centre for Cancer Biology, SA Pathology, Adelaide, Australia

Identity

HGNC
LOCATION
1q41
LOCUSID
ALIAS
CATLPH,PEZ,PTP36,PTPD2
FUSION GENES

DNA/RNA

Atlas Image
Genomic and transcript structure of human PTPN14. A. The genomic arrangement of PTPN14 with vertical bars depicting the location and relative size of exons. Space between exons depicts relative sizes of introns/non-coding regions. B. The mature transcript arrangement of PTPN14. Exons are numbered and coding regions are depicted in light brown, with non-coding regions depicted in red. C. PTPN14 exon length and coding status.

Description

The PTPN14 gene consists of 19 exons and 21 introns divided over 203 kb, including a coding region and 5 and 3 non-coding regions.

Transcription

The PTPN14 transcript is processed into a mature mRNA in excess of 10 kb, estimated by Northern blot analysis (Smith et al., 1995). The mature transcript has a 3561 nucleotide open reading frame and ~9,2 kb 3 UTR followed by a polyadenylation site. No transcript variants have been identified.
Little investigation has been undertaken to elucidate the factors regulating PTPN14 transcription. However, real-time PCR and ChIP sequencing have shown that p63 induces PTPN14 expression by binding to a p63 consensus sequence within intron 3 of PTPN14 (Perez et al., 2007).

Proteins

Atlas Image
Protein structure of PTPN14. A schematic of PTPN14 protein highlighting putative nuclear / mitochondrial localisation signals (red/grey box), the band 4.1 ezrin, radixin, meosin (FERM) homology domain (red), and the tyrosine-phosphatase (PTP) catalytic domain (blue). The linker region also contains an acidic region as well as two PPxY motifs.

Description

PTPN14 is an 1187 amino acid non-receptor protein tyrosine phosphatase of approximately 135 kDa. It possesses an N-terminal FERM (band 4.1, ezrin, radixin, moesin homology) domain and C-terminal catalytic domain, as well as acidic and proline-rich regions in its central uncharacterised region (Smith et al., 1995).
FERM domain: the FERM domain has been shown in other proteins to be important for cytoskeletal association; however a role for the FERM domain in the PTPN14 protein has yet to be described.
Catalytic PTP domain: the crystal structure of the PTPN14 catalytic C-terminal PTP domain has been solved (Barr et al., 2006).
PPxY motifs: Pez contains two PPxY motifs in its central region. These motifs are known to facilitate binding to proteins containing WW domains. Indeed, both PPxY motifs in PTPN14 are critical for binding KIBRA and YAP, components of the Hippo signalling pathway that contain WW domains (Liu et al., 2013; Poernbacher et al., 2012).
Mitochondrial localisation signal: PTPN14 contains a putative mitochondrial localisation signal (MitoProt II), and may be localised to mitochondria in some cell types (Chao et al., 2011).
Atlas Image
Expression of PTPN14.

Localisation

PTPN14 protein has been reported to localise to adherens junctions in confluent human umbilical vein endothelial cells (HUVEC) and translocate to the nucleus in sub-confluent, proliferating HUVEC (Wadham et al., 2000; Wadham et al., 2003). Localisation to the golgi apparatus in epithelial cell types (Wyatt and Khew-Goodall, 2008) and mitochondria in human sperm has also been reported (Chao et al., 2011).

Function

PTPN14 intracellular signaling pathways/processes
Adherens junction integrity: PTPN14 protein has been reported to dephosphorylate the adherens junction protein beta-catenin. Over-expression of a dominant-negative form of PTPN14 caused an increase in phosphorylation at adherens junctions (Wadham et al., 2003), an event linked to adherence junction destabilisation.
TGF-β: PTPN14 promotes epithelial-mesenchymal transition (EMT) via increased TGF-beta production in MDCK epithelial cells (Wyatt et al., 2007)
Lymphangiogenesis: PTPN14 forms a complex with VEGFR3 and is required for normal lymphangiogenesis in human and mouse models (Au et al., 2010).
Hippo signalling: PTPN14 has been shown to interact with Kibra/WWC1 (Poernbacher et al., 2012; Wang et al., 2012) and YAP (Liu et al., 2013; Huang et al., 2012; Wang et al., 2012), two members of the Hippo signalling pathway. In Drosophila, PTPN14 interacts with Kibra via a PPxY:WW domain interaction, to negatively regulate the transcriptional activity of the downstream effector Yorkie, resulting in a decrease in intestinal stem cell proliferation (Poernbacher et al., 2012). Pez interacts with YAP (the mammalian homolog of Drosophila Yorkie), also via a PPxY:WW domain interaction, and regulates its activity by controlling YAP cytoplasmic retention (resulting in a loss of transcription of YAP target genes) (Liu et al., 2013, Huang et al., 2012, Wang et al., 2012).
Mast cell degranulation: PTPN14 siRNA mediated knock-down in mast cells caused a decrease in IgE dependent mast cell degranulation (Zhang et al., 2010).

Homology

PTPN14 belongs to a FERM domain-containing family of non-receptor protein tyrosine phosphatases including PTPN3 (PTPH1), PTPN4 (PTP-MEG1), PTPN13 (PTP-BAS / FAP-1) and PTPN21 (PTPD2). PTPN14 displays a higher degree of homology to PTPN21 than other members of this sub-family (Smith et al., 1995; Alonso et al., 2004).

Mutations

Germinal

A deletion in PTPN14 has been described in a kindred with inherited lymphedema-choanal atresia syndrome, characterised by defects in lymphatic vasculature (Au et al., 2010).

Somatic

Missense mutations in PTPN14 have been reported in sporadic human colorectal cancers (Wang et al., 2004), breast cancers (Sjöblom et al., 2006), and HCV-associated hepatocellular carcinoma (Li et al., 2011).

Implicated in

Entity name
Various cancers
Note
Several studies have identified mutations associated with PTPN14 in colorectal (Wang et al., 2004), breast (Sjöblom et al., 2006) and liver cancers (Li et al., 2011), although the functional consequences of these mutations are yet to be determined.
Entity name
Colorectal cancer
Note
PTPN14 has been shown to interact with and de-phosphorylate residue Y128 of p130 Crk-associated substrate (p130Cas) in colorectal cancer cells (CRC) (Zhang et al., 2012). CRC homozygous for a non-phosphorylatable Y128F mutant form of p130Cas display a reduction in migration,anchorage-independent growth and xenograft tumor growth in nude mice, suggesting that Pez, via p130Cas Y128 dephosphorylation, may function as a tumour suppressor in colorectal cancer.
Entity name
Pancreatic cancer
Note
PTPN14 expression was found to be lower in liver metastases compared to primary tumours in an orthotopic transplantation model of pancreatic adenocarcinoma (Niedergethmann et al., 2007), implicating PTPN14 as a suppressor of metastasis in this model.
Entity name
Epithelial-mesenchymal transition
Note
Over-expression of PTPN14 in epithelial cells (MDCK) resulted in increased TGF-beta secretion and subsequent induction of epithelial-mesenchymal transition (EMT) (Wyatt et al., 2007).
Entity name
Sperm motility
Note
PTPN14 expression in human sperm was correlated with motility, where moderate-motility sperm had less PTPN14 expression than highly-motile sperm (Chao et al., 2011).
Entity name
Lymphedema-choanal atresia syndrome
Note
Analyses of a kindred with autosomal-recessive lyphedema-choanal atresia syndrome showed a loss of function mutation in PTPN14. PTPN14-/- mice developed lymphatic hyperplasia with lymphedema. PTPN14 was also shown to interact with VEGFR3, a signalling receptor essential to lymphangiogenesis (Au et al., 2010).
Entity name
Hereditary haemorrhagic telangiectasia
Note
PTPN14 maps to a chromosomal region that modifies the penetrance of a vascular dysgenesis phenotype in Tgfb1-/- mice, and can modulate angiogenesis in 3D primary endothelial cell culture (Benzinou et al., 2012), suggesting that Pez contributes to angiogenesis, possibly an interaction with the TGF-beta signalling pathway.

Bibliography

Pubmed IDLast YearTitleAuthors
151867722004Protein tyrosine phosphatases in the human genome.Alonso A et al
208262702010Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans.Au AC et al
165348122006Crystal structure of human protein tyrosine phosphatase 14 (PTPN14) at 1.65-A resolution.Barr AJ et al
222336262012Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia.Benzinou M et al
217018402011Protein tyrosine phosphatase non-receptor type 14 is a novel sperm-motility biomarker.Chao HC et al
89447661996Computational method to predict mitochondrially imported proteins and their targeting sequences.Claros MG et al
226890612013YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14.Huang JM et al
218222642011Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma.Li M et al
225252712013PTPN14 interacts with and negatively regulates the oncogenic function of YAP.Liu X et al
179405122007Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model.Niedergethmann M et al
175637512007p63 consensus DNA-binding site: identification, analysis and application into a p63MH algorithm.Perez CA et al
223057522012Drosophila Pez acts in Hippo signaling to restrict intestinal stem cell proliferation.Poernbacher I et al
169599742006The consensus coding sequences of human breast and colorectal cancers.Sjöblom T et al
77339901995Pez: a novel human cDNA encoding protein tyrosine phosphatase- and ezrin-like domains.Smith AL et al
128080482003The protein tyrosine phosphatase Pez is a major phosphatase of adherens junctions and dephosphorylates beta-catenin.Wadham C et al
229486612012PTPN14 is required for the density-dependent control of YAP1.Wang W et al
151559502004Mutational analysis of the tyrosine phosphatome in colorectal cancers.Wang Z et al
186771192008PTP-Pez: a novel regulator of TGFbeta signaling.Wyatt L et al
178932462007The protein tyrosine phosphatase Pez regulates TGFbeta, epithelial-mesenchymal transition, and organ development.Wyatt L et al
204837672010Small interfering RNA screen for phosphatases involved in IgE-mediated mast cell degranulation.Zhang J et al
227107232013Identification and functional characterization of p130Cas as a substrate of protein tyrosine phosphatase nonreceptor 14.Zhang P et al

Other Information

Locus ID:

NCBI: 5784
MIM: 603155
HGNC: 9647
Ensembl: ENSG00000152104

Variants:

dbSNP: 5784
ClinVar: 5784
TCGA: ENSG00000152104
COSMIC: PTPN14

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000152104ENST00000366956Q15678
ENSG00000152104ENST00000543945E2J9M0

Expression (GTEx)

0
5
10
15
20
25
30
35

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
229486612012PTPN14 is required for the density-dependent control of YAP1.70
225252712013PTPN14 interacts with and negatively regulates the oncogenic function of YAP.64
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
226890612013YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14.62
258032292015MiR-21 promotes intrahepatic cholangiocarcinoma proliferation and growth in vitro and in vivo by targeting PTPN14 and PTEN.42
236139712013The tyrosine phosphatase PTPN14 is a negative regulator of YAP activity.35
250232892014PTPN14 forms a complex with Kibra and LATS1 proteins and negatively regulates the YAP oncogenic function.33
290170572017A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer.30
222336262012Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia.24
276513632016High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation.22

Citation

Nicholas Hauschild ; Leila Belle ; Yeesim Khew-Goodall

PTPN14 (protein tyrosine phosphatase, non-receptor type 14)

Atlas Genet Cytogenet Oncol Haematol. 2013-01-01

Online version: http://atlasgeneticsoncology.org/gene/41913/ptpn14id41913ch1q32