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

	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).

	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).
	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).

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