Phosphatase Subfamily PTPN3

Phosphatase Classification: Fold CC1:Superfamily CC1: Family PTP: Subfamily PTPN3

Evolution

The PTPN3 subfamily emerged in holozoa and duplicated in vertebrates. Human has two members of this subfamily, PTPN3/PTPH1 and PTPN4/PTPMEG.

Domain

The PTPN3 subfamily has a domain combination of FERM domain, PEST sequence, PDZ domain and phosphatase domain [1, 2, 3]. PDZ domain can bind to other proteins and modulate the phosphatase domain [4].

Functions

The expression pattern, substrates and interacting partners of PTPN3/PTPH1 and PTPN4 have limited overlap.

PTPN3 (PTPH1)

PTPN3/PTPH1 is widely expressed in different tissues; it is expressed at a relatively higher level in skin and skeletal muscle according to GTEx.

PTPN3/PTPH1 substrates:

• Cell cycle regulator VCP (p97/CDC48) [5].
• T cell receptor zeta subunit [6].
• Estrogen receptor at Tyr-537 [7].
• Epidermal growth factor receptor (EGFR) pathway substrate 15 (Eps15) at Tyr-849[8] .
• p38γ mitogen-activated protein kinase (MAPK). The interaction is mediated through PDZ binding [9], and vice versa, p38γ is also a kinase of PTPN3 [10].

PTPN3/PTPH1 interacts with and regulates Cardiac sodium channel Na(v)1.5. The interaction is mediated by the PDZ domain of PTPN3 and the PDZ-domain binding motif of Na(v)1.5 [11]. PTPN3/PTPH1 is a negative regulator of Tumor necrosis factor alpha-convertase (TACE), a metalloprotease-disintegrin involved in the ectodomain shedding of several proteins and is critical for proper murine development. The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE [12]. PTPN3/PTPH1 interacts with adaptor protein 14-3-3beta in a manner dependent on the phosphorylation state of PTPN3 [13]. PTPN3/PTPH1 binds to vitamin D receptor (VDR) and increases VDR's cytoplasmic accumulation, leading to their mutual stabilization and stimulating breast cancer growth [14]. PTPN3/PTPH1 controls growth hormone receptor (GHR) signaling [15].

PTPN3/PTPH1 is implicated in breast cancer [7, 14], intrahepatic cholangiocarcinoma [16], and human hepatocellular carcinomas [17].

PTPN4 (PTPMEG)

PTPN4/PTPMEG primarily locates in the membrane and cytoskeleton [18, 19]. PTPN4/PTPMEG has been shown to be specifically expressed in testis [20]. However, RNA-seq data in GTEx shows it is widely expressed in different tissues, most abundantly in cerebellum and the expression level in testis is close to the average.

PTPN4 dephosphorylates T cell receptor (TCR) at ITAM motifs, a conserved signaling motif and are present in one or more copies in the cytoplasmic tails of the CD3 γ, δ, ε and TCR ζ subunits [21].

PTPN4 dephosphorylates TRIF-related adaptor molecule (TRAM, also known as TICAM2), therefore inhibiting TRIF-dependent TLR4 pathway [22].

PTPN4/PTPMEG interacts with but does not directly phosphorylates glutamate receptor delta 2 and epsilon subunits [23].

References

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