Alternative titles; symbols
HGNC Approved Gene Symbol: PTPN12
Cytogenetic location: 7q11.23 Genomic coordinates (GRCh38): 7:77,537,295-77,640,069 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q11.23 | Colon cancer, somatic | 114500 | 3 |
Protein tyrosine phosphatases (PTPs), such as PTPN12, and protein tyrosine kinases (PTKs) (e.g., PTK2; 600758) are involved in the regulation of tyrosine phosphorylation-mediated signaling. Such signaling is critical for the regulation of cell proliferation, differentiation, and neoplastic transformation. Tyrosine-phosphorylated proteins can be specifically dephosphorylated through the action of PTPs, which therefore are likely to have as important a role as PTKs in the control of cellular growth and differentiation (summary by Takekawa et al., 1992)
From an adult cDNA library, Takekawa et al. (1992) isolated a cDNA encoding PTPG1, a predicted 88-kD protein.
By PCR of skeletal muscle RNA, followed by screening a HeLa cell cDNA library, Yang et al. (1993) cloned PTPN12, which they called PTP-PEST. The deduced 780-amino acid protein contains a PTP catalytic domain in its N-terminal half and 4 potential PEST sequences, which are characteristic of proteins with short intracellular half-lives, in its C-terminal half. The PTPN12 catalytic domain shares about 35% amino acid identity with other PTP catalytic domains and contains a conserved cysteine essential for enzymatic activity. Northern blot analysis showed broad distribution of a 3.8-kb transcript in various human cell lines, although expression was absent in Jurkat leukemic T cells and 293 kidney cells.
Yang et al. (1993) expressed a GST fusion protein containing the N-terminal catalytic domain of PTPN12 in E. coli and demonstrated intrinsic activity in vitro against a variety of phosphotyrosine-containing substrates, including BIRK, the autophosphorylated cytoplasmic kinase domain of the insulin receptor beta subunit (INSR; 147670). For all substrates, the pH optimum was 6 to 7. PTPN12 was unable to dephosphorylate phosphoseryl-phosphorylase A (see PYGL; 613741), suggesting that PTPN12 activity is specific for phosphotyrosines. Northern blot analysis showed that insulin (INS; 176730) stimulation of A204 rhabdomyosarcoma cells increased PTPN12 mRNA levels 4-fold compared with controls.
Cong et al. (2000) showed that PSTPIP1 (606347) bridges ABL (189980) to the PEST-type PTPs. Several experiments suggested that the PEST-type PTPs negatively regulate ABL activity: ABL was hyperphosphorylated in PTP-PEST-deficient cells; disruption of the ABL-PSTPIP1-PEST-type PTP ternary complex by overexpression of mutants increased ABL phosphotyrosine content; and PDGF (see 190040)-induced ABL kinase activation was prolonged in PTP-PEST-deficient cells. The authors concluded that dephosphorylation of ABL by PSTPIP1-directed PEST-type PTPs represents a novel mechanism by which ABL activity is regulated.
Wise et al. (2002) identified missense mutations in the PSTPIP1 gene in 2 reported families with PAPA syndrome (604416) and familial recurrent arthritis. PSTPIP1 and its murine ortholog are adaptor proteins known to interact with PEST-type PTPs such as PTPN12. Yeast 2-hybrid assays demonstrated severely reduced binding between PTPN12 and the 2 mutant proteins of PSTPIP1. Previous evidence supported the integral role of PSTPIP1 and its interacting proteins in actin reorganization during cytoskeletal-mediated events. The authors hypothesized that the disease-causing mutations identified compromise physiologic signaling necessary for the maintenance of a proper inflammatory response.
Using short hairpin RNA, Sun et al. (2011) showed that downregulation of PTPN12 disrupted 3-dimensional acinar formation by human mammary epithelial cells (HMECs). Conversely, overexpression of PTPN12 suppressed tumor transformation in SV40-transformed HMECs. Suppression of transformation was due to PTPN12-mediated inhibition of several receptor tyrosine kinases and an EGFR (131550)/HER2 (ERBB2; 164870)-MAPK (see 176948) signaling axis. PTPN12 expression was inactivated by mutation in a subset of triple-negative breast cancer tissues and cell lines, which are defined by the absence of ER (ESR1; 133430) and PR (PGR; 607311) expression or HER2 amplification. Protein expression of PTPN12 was controlled by microRNA-124 (MIR124; see 609327) via 3 evolutionarily conserved MIR124-binding sites in the PTPN12 3-prime UTR. Transgenic expression of REST (600571), a transcriptional repressor of MIR124, increased PTPN12 protein levels in triple-negative breast cancer cell lines. Sun et al. (2011) proposed a model in which REST positively regulates PTPN12 expression by downregulating MIR124, a negative regulator of PTPN12.
Charest et al. (1995) determined that the mouse PTPN12 gene contains 18 exons spanning about 90 kb of DNA.
By fluorescence in situ hybridization (FISH), Takekawa et al. (1994) mapped the PTPN12 gene to 7q11.23. Charest et al. (1995) used FISH to map the mouse Ptpn12 gene to chromosome 5A3 to B, a region with homology of synteny to human chromosome 7q11.23.
The potential importance of PTPG1 in tumorigenesis was investigated by Takekawa et al. (1994), who sought abnormalities of the PTPG1 transcript in various human cancer cell lines by use of RT-PCR. In a colorectal carcinoma cell line, DLD-1, they found 3 aberrant transcripts: a missense point mutation, a 77-bp deletion, and a 173-bp deletion.
In a colorectal carcinoma cell line (see 114500), DLD-1, Takekawa et al. (1994) found 3 aberrant transcripts by RT-PCR. Sequencing in one demonstrated an A-to-G transition at nucleotide 201, predicting a change of codon 61 from lysine to arginine.
Charest, A., Wagner, J., Muise, E. S., Heng, H. H. Q., Tremblay, M. L. Structure of the murine MPTP-PEST gene: genomic organization and chromosomal mapping. Genomics 28: 501-507, 1995. [PubMed: 7490087] [Full Text: https://doi.org/10.1006/geno.1995.1181]
Cong, F., Spencer, S., Cote, J.-F., Wu, Y., Tremblay, M. L., Lasky, L. A., Goff, S. P. Cytoskeletal protein PSTPIP1 directs the PEST-type protein tyrosine phosphatase to the c-Abl kinase to mediate Abl dephosphorylation. Molec. Cell 6: 1413-1423, 2000. [PubMed: 11163214] [Full Text: https://doi.org/10.1016/s1097-2765(00)00138-6]
Spencer, S., Dowbenko, D., Cheng, J., Li, W., Brush, J., Utzig, S., Simanis, V., Lasky, L. A. PSTPIP: a tyrosine phosphorylated cleavage furrow-associated protein that is a substrate for PEST tyrosine phosphatase. J. Cell Biol. 138: 845-860, 1997. [PubMed: 9265651] [Full Text: https://doi.org/10.1083/jcb.138.4.845]
Sun, T., Aceto, N., Meerbrey, K. L., Kessler, J. D., Zhou, C., Migliaccio, I., Nguyen, D. X., Pavlova, N. N., Botero, M., Huang, J., Bernardi, R. J., Schmitt, E., and 16 others. Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase. Cell 144: 703-718, 2011. [PubMed: 21376233] [Full Text: https://doi.org/10.1016/j.cell.2011.02.003]
Takekawa, M., Itoh, F., Hinoda, Y., Adachi, M., Ariyama, T., Inazawa, J., Imai, K., Yachi, A. Chromosomal localization of the protein tyrosine phosphatase G1 gene and characterization of the aberrant transcripts in human colon cancer cells. FEBS Lett. 339: 222-228, 1994. [PubMed: 7509295] [Full Text: https://doi.org/10.1016/0014-5793(94)80420-6]
Takekawa, M., Itoh, F., Hinoda, Y., Arimura, Y., Toyota, M., Sekiya, M., Adachi, M., Imai, K., Yachi, A. Cloning and characterization of a human cDNA encoding a novel putative cytoplasmic protein-tyrosine-phosphatase. Biochem. Biophys. Res. Commun. 189: 1223-1230, 1992. [PubMed: 1472029] [Full Text: https://doi.org/10.1016/0006-291x(92)92335-u]
Wise, C. A., Gillum, J. D., Seidman, C. E., Lindor, N. M., Veile, R., Bashiardes, S., Lovett, M. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum. Molec. Genet. 11: 961-969, 2002. [PubMed: 11971877] [Full Text: https://doi.org/10.1093/hmg/11.8.961]
Yang, Q., Co, D., Sommercorn, J., Tonks, N. K. Cloning and expression of PTP-PEST: a novel, human, nontransmembrane protein tyrosine phosphatase. J. Biol. Chem. 268: 6622-6628, 1993. Note: Erratum: J. Biol. Chem. 268: 17650 only, 1993. [PubMed: 8454633]