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 [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33]