Alternative titles; symbols
HGNC Approved Gene Symbol: PTPN6
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:6,946,577-6,961,316 (from NCBI)
The growth and functional responses of hematopoietic cells are regulated through tyrosine phosphorylation of proteins. Using a PCR approach, Yi et al. (1991) identified 3 novel tyrosine protein phosphatases in hematopoietic cells. One of these, expressed predominantly in hematopoietic cells, was termed hematopoietic cell phosphatase (HCPH). From a pre-B-cell-derived library, Matthews et al. (1992) cloned the mouse PTPN6 cDNA, which they designated SHP (Src homology region 2-domain phosphatase). Yi et al. (1992) obtained complete cDNAs for both the human and murine HCPH genes. The human gene was also cloned from a breast cancer cell line and termed PTP1C by Shen et al. (1991). PTP1C encodes a cytoplasmic protein that contains a phosphatase-catalytic domain in the C-terminal region and 2 tandemly repeated, src-homology 2 (SH2) domains in the N-terminal region. SH2 domains were first identified in the SRC gene family and found in a variety of proteins involved in signal transduction. The SH2 domains may recognize phosphorylated tyrosine residues and direct protein-protein associations.
Banville et al. (1995) demonstrated that the PTPN6 gene consists of 17 exons spanning 17 kb of DNA. Three nonhematopoietic PTPN6 transcripts were identified in a variety of cell lines and were shown to be transcribed from a common promoter. The hematopoietic form of the PTPN6 transcript is initiated at a downstream promoter separated by 7 kb from the upstream promoter. This downstream promoter is active exclusively in cells of the hematopoietic lineage.
Yi et al. (1992) mapped the human HCPH gene to chromosome 12p13-p12 by fluorescence in situ hybridization. By study of panels of somatic cell hybrids and fluorescence in situ hybridization, Plutzky et al. (1992) determined that the gene encoding the nontransmembrane protein-tyrosine phosphatase of the nonreceptor type 6 is located in region 12p13.
Using a genomic probe in interspecific backcross analysis, Yi et al. (1992) mapped the murine Hcph gene to chromosome 6 where it was found to be tightly linked to the Tnfr2 and Ly4 genes.
Plutzky et al. (1992) suggested that since PTPN6 is expressed at high levels in hematopoietic cells of all lineages and its expression is induced early in hematopoietic differentiation, and since 12p13 is a region commonly involved in leukemia-associated chromosomal abnormalities, altered expression and/or structure of PTPN6 may play a role in leukemogenesis.
T-cell lymphomas lose expression of SHP1 due to DNA methylation of its promoter. Zhang et al. (2005) demonstrated that malignant T cells expressed DNMT1 (126375) and that STAT3 (102582) could bind sites in the SHP1 promoter in vitro. STAT3, DNMT1, and HDAC1 (601241) formed complexes and bound to the SHP1 promoter in vivo. Antisense DNMT1 and STAT3 small interfering RNA induced DNA demethylation in malignant T cells and expression of SHP1. Zhang et al. (2005) concluded that STAT3 may transform cells by inducing epigenetic silencing of SHP1 in cooperation with DNMT1 and HDAC1.
Combining computer modeling and single-cell measurements, Feinerman et al. (2008) examined how endogenous variation in the expression levels of signaling proteins might affect antigen responsiveness during T-cell activation. They found that the CD8 (186910) coreceptor fine-tuned activation thresholds, whereas SHP1 digitally regulated cell responsiveness. Stochastic variation in expression of these proteins generated substantial diversity of activation within a clonal population of T cells, but coregulation of CD8 and SHP1 levels ultimately limited this very diversity. Feinerman et al. (2008) concluded that these findings revealed how eukaryotic cells can draw on regulated variation in gene expression to achieve phenotypic variability in a controlled manner.
In a cultured bovine retinal pericyte model, Geraldes et al. (2009) demonstrated that hyperglycemia persistently activates PRKCD (176977) and p38-alpha MAPK (MAPK14; 600289), thus increasing expression of SHP1, and that this occurs independently of NFKB (see 164011) activation. This signaling cascade leads to PDGF receptor-beta (PDGFRB; 173410) dephosphorylation and a reduction in downstream signaling from this receptor, resulting in pericyte apoptosis, the most specific vascular histopathology associated with diabetic complications. The authors observed increased PRKCD activity and an increase in the number of acellular capillaries in diabetic mouse retinas, which were not reversible with insulin treatment that achieved normoglycemia. Unlike diabetic age-matched wildtype mice, diabetic Prkcd -/- mice did not show activation of MAPK14 or SHP1, inhibition of PDGFB (190040) signaling in vascular cells, or the presence of acellular capillaries. The authors also observed PRKCD, MAPK14, and SHP1 activation in brain pericytes and in the renal cortex of diabetic mice. Geraldes et al. (2009) concluded that this represents a new signaling pathway by which hyperglycemia can induce PDGFB resistance and increased vascular cell apoptosis to cause diabetic vascular complications.
Khalil et al. (2012) showed that most proliferating germinal center B cells do not demonstrate active B cell receptor signaling. Rather, spontaneous and induced signaling was limited by increased phosphatase activity. Accordingly, both SHP1 and SH2 domain-containing inositol 5-phosphatase (SHIP1; 601582) were hyperphosphorylated in germinal center cells and remained colocalized with B cell receptors after ligation. Furthermore, SHP1 was required for germinal cell maintenance. Intriguingly, germinal center B cells in the cell cycle G2 period regained responsiveness to B cell receptor stimulation.
Beghini et al. (2000) examined the expression of PTPN6 in CD34+/CD117+ blasts from acute myeloid leukemia patients. They identified and cloned novel PTPN6 mRNA species, derived from aberrant splicing within the N-SH2 domain leading to retention of intron 3. Sequence analysis revealed an A-to-G conversion of A7866, which represents the putative branch site in IVS3 of PTPN6 mRNA. The level of the aberrant intron-retaining splice variant, evaluated by semiquantitative RT-PCR, was lower in CD117 +/- AML bone marrow mononuclear cells at remission than at diagnosis, suggesting an involvement of posttranscriptional PTPN6 processing in leukemogenesis.
Mice with the recessive 'moth eaten' (me) or the allelic 'viable moth eaten' mutations express a severe autoimmune and immunodeficiency syndrome. Tsui et al. (1993) showed that the basic defect involves lesions in the gene that encodes hematopoietic cell phosphatase. Shultz et al. (1993) showed that 2 allelic 'motheaten' mutations result in aberrant splicing of the Hcph transcript. Thus, 'motheaten' was the first animal model for a specific protein-tyrosine phosphatase deficiency, useful in determining the precise role of HCPH in hematopoiesis.
Kamata et al. (2003) found that CD4 T cells in mice heterozygous for the motheaten mutation express about half the normal amount of SHP1. Th2 cell differentiation and Th2 cytokine production in CD4 T cells and specific cytokine production in mast cells were enhanced in these mice. Eosinophilic infiltration and enhanced airway hyperresponsiveness were also noted in OVA-sensitized heterozygous mice, but only after OVA inhalation. Kamata et al. (2003) suggested that SHP1 may be a negative regulator in the development of allergic responses such as allergic asthma.
Dubois et al. (2006) demonstrated that 'viable motheaten' mice bearing a functionally deficient SHP1 protein are markedly glucose tolerant and insulin sensitive compared to wildtype littermates, due to enhanced insulin receptor signaling to IRS (see 147545)-PI3K (see PIK3CA; 171834)-Akt (164730) in liver and muscle and increased phosphorylation of CEACAM1 (109770). This metabolic phenotype was recapitulated in normal mice through adenoviral expression of a dominant-negative inactive form of SHP1 in the liver or hepatic knockdown of SHP1 by small hairpin RNA-mediated gene silencing. Dubois et al. (2006) concluded that SHP1 plays a crucial role in negatively modulating insulin action and clearance in the liver, thereby regulating whole-body glucose homeostasis.
Using chemical mutagenesis, Croker et al. (2008) obtained mice with a recessive phenotype they termed 'spin,' for spontaneous inflammation. Homozygous spin mice had chronic lesions in feet, salivary glands, and lungs and antichromatin antibodies. Spin mice had enhanced resistance to Listeria monocytogenes infection. Testing the suppressive effects of mutations at other loci showed that the autoinflammatory phenotype of spin mice required Myd88 (602170), Irak4 (606883), and Il1r1 (147810), but not Ticam1 (607601), Stat1 (600555), or Tnf (191160). Spin mice derived into a germ-free environment did not show either autoimmune or autoinflammatory phenotypes. Positional cloning mapped spin to the distal region of chromosome 6, and Croker et al. (2008) identified a T-to-A transversion in exon 5 of the Ptpn6 gene, resulting in a tyr208-to-asn (Y208N) substitution in the N-terminal SH2 domain of the protein. Croker et al. (2008) concluded that the spin phenotype is due to a viable hypomorphic allele of Ptpn6 and that spin autoimmunity is driven by commensal microbes acting through the Tlr (e.g., TLR4; 603030) pathway requiring Myd88, Irak4, and Il1r1.
PTPN6(spin) mice spontaneously develop a severe inflammatory syndrome that resembles neutrophilic dermatosis in humans and is characterized by persistent footpad swelling and suppurative inflammation. Lukens et al. (2013) reported that receptor-interacting protein-1 (RIP1; 603453)-regulated interleukin 1-alpha (IL1A; 147760) production by hematopoietic cells critically mediates chronic inflammatory disease in Ptpn6(spin) mice, whereas inflammasome signaling and IL1-beta (147720)-mediated events are dispensable. IL1A was also crucial for exacerbated inflammatory responses and unremitting tissue damage upon footpad microabrasion of Ptpn6(spin) mice. Notably, pharmacologic and genetic blockade of the kinase RIP1 protected against wound-induced inflammation and tissue damage in Ptpn6(spin) mice, whereas RIP3 (605817) deletion failed to do so. Moreover, RIP1-mediated inflammatory cytokine production was attenuated by NF-kappa-B (see 164011) and ERK (see 601795) inhibition. Lukens et al. (2013) concluded that wound-induced tissue damage and chronic inflammation in Ptpn6(spin) mice are critically dependent on RIP1-mediated IL1-alpha production, whereas inflammasome signaling and RIP3-mediated necroptosis are dispensable.
Banville, D., Stocco, R., Shen, S.-H. Human protein tyrosine phosphatase 1C (PTPN6) gene structure: alternate promoter usage and exon skipping generate multiple transcripts. Genomics 27: 165-173, 1995. [PubMed: 7665165] [Full Text: https://doi.org/10.1006/geno.1995.1020]
Beghini, A., Ripamonti, C. B., Peterlongo, P., Roversi, G., Cairoli, R., Morra, E., Larizza, L. RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia. Hum. Molec. Genet. 9: 2297-2304, 2000. [PubMed: 11001933] [Full Text: https://doi.org/10.1093/oxfordjournals.hmg.a018921]
Croker, B. A., Lawson, B. R., Rutschmann, S., Berger, M., Eidenschenk, C., Blasius, A. L., Moresco, E. M. Y., Sovath, S., Cengia, L., Shultz, L. D., Theofilopoulos, A. N., Pettersson, S., Beutler, B. A. Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and microbial trigger. Proc. Nat. Acad. Sci. 105: 15028-15033, 2008. Note: Erratum: Proc. Nat. Acad. Sci. 105: 19561 only, 2008. [PubMed: 18806225] [Full Text: https://doi.org/10.1073/pnas.0806619105]
Dubois, M.-J., Bergeron, S., Kim, H.-J., Dombrowski, L., Perreault, M., Fournes, B., Faure, R., Olivier, M., Beauchemin, N., Shulman, G. I., Siminovitch, K. A., Kim, J. K., Marette, A. The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis. Nature Med. 12: 549-556, 2006. [PubMed: 16617349] [Full Text: https://doi.org/10.1038/nm1397]
Feinerman, O., Veiga, J., Dorfman, J. R., Germain, R. N., Altan-Bonnet, G. Variability and robustness in T cell activation from regulated heterogeneity in protein levels. Science 321: 1081-1084, 2008. [PubMed: 18719282] [Full Text: https://doi.org/10.1126/science.1158013]
Geraldes, P., Hiraoka-Yamamoto, J., Matsumoto, M., Clermont, A., Leitges, M., Marette, A., Aiello, L. P., Kern, T. S., King, G. L. Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nature Med. 15: 1298-1306, 2009. [PubMed: 19881493] [Full Text: https://doi.org/10.1038/nm.2052]
Kamata, T., Yamashita, M., Kimura, M., Murata, K., Inami, M., Shimizu, C., Sugaya, K., Wang, C.-R., Taniguchi, M., Nakayama, T. Src homology 2 domain-containing tyrosine phosphatase SHP-1 controls the development of allergic airway inflammation. J. Clin. Invest. 111: 109-119, 2003. [PubMed: 12511594] [Full Text: https://doi.org/10.1172/JCI15719]
Khalil, A. M., Cambier, J. C., Shlomchik, M. J. B cell receptor signal transduction in the GC is short-circuited by high phosphatase activity. Science 336: 1178-1181, 2012. [PubMed: 22555432] [Full Text: https://doi.org/10.1126/science.1213368]
Lukens, J. R., Vogel, P., Johnson, G. R., Kelliher, M. A., Iwakura, Y., Lamkanfi, M., Kanneganti, T. D. RIP1-driven autoinflammation targets IL-1-alpha independently of inflammasomes and RIP3. Nature 498: 224-227, 2013. [PubMed: 23708968] [Full Text: https://doi.org/10.1038/nature12174]
Matthews, R. J., Bowne, D. B., Flores, E., Thomas, M. L. Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences. Molec. Cell. Biol. 12: 2396-2405, 1992. [PubMed: 1373816] [Full Text: https://doi.org/10.1128/mcb.12.5.2396-2405.1992]
Plutzky, J., Neel, B. G., Rosenberg, R. D., Eddy, R. L., Byers, M. G., Jani-Sait, S., Shows, T. B. Chromosomal localization of an SH2-containing tyrosine phosphatase (PTPN6). Genomics 13: 869-872, 1992. [PubMed: 1639416] [Full Text: https://doi.org/10.1016/0888-7543(92)90172-o]
Shen, S.-H., Bastien, L., Posner, B. I., Chretien, P. A protein-tyrosine phosphatase with sequence similarity to the SH2 domain of the protein-tyrosine kinases. Nature 352: 736-739, 1991. Note: Erratum: Nature: 353: 868 only, 1991. [PubMed: 1652101] [Full Text: https://doi.org/10.1038/352736a0]
Shultz, L. D., Schweitzer, P. A., Rajan, T. V., Yi, T., Ihle, J. N., Matthews, R. J., Thomas, M. L., Beier, D. R. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73: 1445-1454, 1993. [PubMed: 8324828] [Full Text: https://doi.org/10.1016/0092-8674(93)90369-2]
Tsui, H. W., Siminovitch, K. A., de Souza, L., Tsui, F. W. L. Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nature Genet. 4: 124-129, 1993. [PubMed: 8348149] [Full Text: https://doi.org/10.1038/ng0693-124]
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Zhang, Q., Wang, H. Y., Marzec, M., Raghunath, P. N., Nagasawa, T., Wasik, M. A. STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc. Nat. Acad. Sci. 102: 6948-6953, 2005. [PubMed: 15870198] [Full Text: https://doi.org/10.1073/pnas.0501959102]