cDNA isolated from a human T-cell library encodes a member of the protein-tyrosine-phosphatase family.

Cool, D. E.; Tonks, Nicholas K.; Charbonneau, Harry; Walsh, Kenneth A.; Fischer, Edmond H.; Krebs, Edwin G.

doi:10.1073/pnas.86.14.5257

Cited by 281 publications

(177 citation statements)

References 33 publications

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“…While expression of PTPN2 is highest in cells of the hematopoietic lineage, it is expressed ubiquitously throughout the body and as early as day e8.5 of development in mouse embryos [43,44]. Two isoforms of PTPN2 are expressed in human cells via alternative splicing; a 45kD variant (387 amino acids) which results from correct splicing of exon 9 to the terminal exon 10, and a 48kD variant which does not splice exon 9 to exon 10, but rather continues translation into intron 9, where a stop codon terminates the protein at amino acid 415 [43,44]. The subcellular localizations of the 45kD and 48kD variants differ as a result of these alternative C-terminal sequences, and thus impact their substrate selection [45].…”

Section: Known Function Of Ptpn2mentioning

confidence: 99%

“…The PTPN2 gene encodes a non-receptor protein tyrosine phosphatase and was originally cloned from a human T cell cDNA library, hence the alternative name T cell protein tyrosine phosphatase (TCPTP) [43]. While expression of PTPN2 is highest in cells of the hematopoietic lineage, it is expressed ubiquitously throughout the body and as early as day e8.5 of development in mouse embryos [43,44].…”

Section: Known Function Of Ptpn2mentioning

confidence: 99%

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Protein Tyrosine Phosphatases and Type 1 Diabetes: Genetic and Functional Implications of PTPN2 and PTPN22

Cerosaletti

Buckner

2012

Rev Diabet Stud

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Protein tyrosine phosphatases (PTPs) play a central role in modulating the transduction of cellular signals, including the cells of the immune system. Several PTPs, PTPN22, PTPN2, and UBASH3A, have been associated with risk of type 1 diabetes (T1D) by genome wide association studies. Based on the current understanding of PTPs, it is clear that these variants impact antigen receptor signaling and cytokine signaling. This impact likely contributes to the development and progression of autoimmunity through multiple mechanisms, including failures of central and peripheral tolerance and the promotion of proinflammatory T cell responses. In this review, we discuss the genetic and functional implications of two of these PTPs, PTPN22 and PTPN2, in the development of T1D. We describe the known roles of these proteins in immune function, and how the expression and function of these proteins is altered by the genetic variants associated with T1D. Yet, there are still controversies in the field that require further study and the development of new approaches to extend our understanding of these PTP variants, with the goal of using the information gained to improve our ability to predict and cure T1D.

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Section: Known Function Of Ptpn2mentioning

confidence: 99%

Section: Known Function Of Ptpn2mentioning

confidence: 99%

Protein Tyrosine Phosphatases and Type 1 Diabetes: Genetic and Functional Implications of PTPN2 and PTPN22

Cerosaletti

Buckner

2012

Rev Diabet Stud

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“…Although originally cloned from a human cDNA Tcell library, it is ubiquitously expressed at all stages of mammalian development and in most adult tissues (Cool et al, 1989, Mosinger et al, 1992, IbarraSaÂ nchez et al, 2000, Tonks and Neel, 2001). TC-PTP contains a nuclear localization signal at its carboxyl terminus that localizes the enzyme to the nucleus (Tillmann et al, 1994;Lorenzen et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Murine embryonic fibroblasts lacking TC-PTP display delayed G1 phase through defective NF-κB activation

et al. 2001

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“…Inhibitors against the enzyme must thus be not only potent but also selective. Sequence alignment of amino acids residues within the PTPs catalytic domain shows that, in general, all phosphatases have less than 40% identity to PTP-1B: a remarkable exception is the T-cell protein-tyrosine phosphatase (TCPTP), which has a 72% identity (11)(12)(13)(14). Inhibitors that target PTP-1B and incorporate previously identified selectivity determinants (15)(16)(17) are generally selective (Ͼ30-fold) over all PTPs tested but are equipotent on TCPTP.…”

mentioning

confidence: 99%

Conformation-assisted Inhibition of Protein-tyrosine Phosphatase-1B Elicits Inhibitor Selectivity over T-cell Protein-tyrosine Phosphatase

Asante‐Appiah¹,

Patel

Desponts³

et al. 2006

Journal of Biological Chemistry

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PTP-1B represents an attractive target for the treatment of type 2 diabetes and obesity. Given the role that protein phosphatases play in the regulation of many biologically relevant processes, inhibitors against PTP-1B must be not only potent, but also selective. It has been extremely difficult to synthesize inhibitors that are selective over the highly homologous TCPTP. We have successfully exploited the conservative Leu 119 to Val substitution between the two enzymes to synthesize a PTP-1B inhibitor that is an order of magnitude more selective over TCPTP. Structural analyses of PTP-1B/inhibitor complexes show a conformation-assisted inhibition mechanism as the basis for selectivity. Such an inhibitory mechanism may be applicable to other homologous enzymes.The quest for agents that can intervene in type 2 diabetes continues to be a major research focus and challenge in many laboratories. As impaired insulin action is an underlying mechanism in type 2 diabetes, the insulin signaling pathway has naturally been the focus of research in attempts to identify suitable therapeutic target(s) for drug intervention against the disease. Insulin signaling begins with the activation of the insulin receptor (IR) via tyrosine phosphorylation and culminates in the uptake of glucose into cells by the glucose transporter, Glut4 (1). The activated IR must then be deactivated and returned to a basal state, a process that is believed to involve protein-tyrosine phosphatase-1B (PTP-1B).4 PTP-1B has been shown to directly interact with the activated insulin receptor (2-6). Disruption of the gene that codes for PTP-1B in mice results in sensitivity to insulin and also increased resistance to diet-induced obesity (7,8). This phosphatase is therefore a very attractive therapeutic target for the treatment not only of type 2 diabetes but also of obesity. Predictably, there has been an intense research effort by many groups to identify potent and selective inhibitors of PTP-1B (for recent reviews, see Refs. 9 and 10). PTP-1B belongs to the proteintyrosine phosphatase (PTP) superfamily of enzymes, which includes ϳ100 members involved in signal transduction and regulation of cellular processes such as growth, differentiation, and proliferation. Inhibitors against the enzyme must thus be not only potent but also selective. Sequence alignment of amino acids residues within the PTPs catalytic domain shows that, in general, all phosphatases have less than 40% identity to PTP-1B: a remarkable exception is the T-cell protein-tyrosine phosphatase (TCPTP), which has a 72% identity (11)(12)(13)(14). Inhibitors that target PTP-1B and incorporate previously identified selectivity determinants (15-17) are generally selective (Ͼ30-fold) over all PTPs tested but are equipotent on TCPTP. Although it is not evident that co-inhibition of TCPTP (with PTP-1B) will result in serious adverse effects, mice lacking the TCPTP gene die within 3-5 weeks after birth from defects in hematopoiesis and immune function (18). Hence, it is highly desirable to design PTP-1...

show abstract

cDNA isolated from a human T-cell library encodes a member of the protein-tyrosine-phosphatase family.

Cited by 281 publications

References 33 publications

Protein Tyrosine Phosphatases and Type 1 Diabetes: Genetic and Functional Implications of PTPN2 and PTPN22

Protein Tyrosine Phosphatases and Type 1 Diabetes: Genetic and Functional Implications of PTPN2 and PTPN22

Murine embryonic fibroblasts lacking TC-PTP display delayed G1 phase through defective NF-κB activation

Conformation-assisted Inhibition of Protein-tyrosine Phosphatase-1B Elicits Inhibitor Selectivity over T-cell Protein-tyrosine Phosphatase

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