PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Front Biosci. Author manuscript; available in PMC Dec 9, 2008.
Published in final edited form as:
PMCID: PMC2599796
NIHMSID: NIHMS80980
Protein tyrosine phosphatases in the JAK/STAT pathway
Dan Xu1,2 and Cheng-Kui Qu1
1 Department of Medicine, Division of Hematology/Oncology, Case Comprehensive Cancer Center, Center for Stem Cell and Regenerative Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA
2 Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
Send correspondence to: Cheng-Kui Qu, M.D., Ph.D., Department of Medicine, Case Comprehensive Cancer Center, Center for Stem Cell and Regenerative Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106. Tel: (216) 368 3361; Fax: (216) 368 1166; E-mail: cxq6/at/case.edu
1. ABSTRACT
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is crucial in controlling cellular activities in response to extracellular cytokines. Dysfunctions of the JAK/STAT pathway result in various hematopoietic and immune disorders. The central events in regulating this pathway are tyrosine phosphorylation and dephosphorylation of the signaling components, which are carried out by protein tyrosine kinases and protein tyrosine phosphatases (PTP), respectively. Here, we review recent advances in the regulatory roles of PTPs, in particular, SHP2 phosphatase, in the JAK/STAT signaling pathway.
Keywords: JAK, STAT, SHP2, Cytokine, Signal transduction, Hematopoiesis
Intracellular signal transduction pathways are essential for connecting extracellular cytokine stimulations to appropriate cellular responses, such as proliferation, differentiation, and apoptosis. One of the most important pathways activated by cytokines is the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, which was initially discovered in the studies on gene induction by interferon (IFN) (1). It is now clear that protein phosphorylation and dephosphorylation play a central role in controlling the activity of the JAK/STAT pathway. The majority of phosphorylation and dephosphorylation occur at tyrosine residues of the component proteins, which are carried out by protein tyrosine kinases and protein tyrosine phosphatases (PTP), respectively (24). This short article summarizes latest insights into how PTPs, including SHP2, SHP1, CD45, PTP1B, T-cell PTP (TC-PTP), PTPRT, and PTPBL, regulate the JAK/STAT pathway.
In the current model of the JAK/STAT signaling pathway, the engagement between a cytokine and its cell surface receptor results in receptor oligomerization and subsequent activation of receptor-associated JAK tyrosine kinases. Activated JAKs phosphorylate specific tyrosine resides in the cytoplasmic domain of the receptor which in turn serves as the docking sites for cytoplasmic transcription factors known as STATs. STATs are therefore recruited to the phosphorylated receptor and subsequently phosphorylated by JAKs. The phosphorylated STATs then dimerize, leave the receptor, and translocate to the nucleus where they activate gene transcription (5, 6). In mammalian cells, four JAK members (JAK1, JAK2, JAK3, and TYK2) have been identified. Each JAK contains a conserved kinase domain and a catalytically-inactive domain at the carboxyl (C-) terminus which might regulate the activity of the kinase domain. There are seven members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6) in the mammalian STAT family. Each of them contains a DNA-binding domain, a transactivation domain located at the C-terminus (7, 8), and a SRC homology 2 (SH2) domain. The SH2 domain is required for STAT activation and dimerization (9, 10) while the amino (N-) terminal region of STAT is involved in the formation of STAT tetramers (11) and tyrosine dephosphorylation (12). Genetic knockout studies have revealed various but specific functions of JAKs and STATs. One who is interested in details about the structures and functions of JAKs and STATs could look at the reviews (2, 1315). The following sections of this review will discuss how PTPs regulate JAK/STAT signaling with a focus on the SHP2 phosphatase, since the role of SHP2 in this context is more complicated than other PTPs.
3.1. SHP2
Structure, regulation, and function
SHP2 is a ubiquitously expressed SH2 domain-containing PTP. It contains two tandem SH2 domains (N-SH2 and C-SH2), a classic tyrosine phosphatase domain at the C-terminus, and a C-terminal tail with two important tyrosine resides (Tyr542 and Tyr580) and some other functional motifs (1619). The SH2 domains, in particular N-SH2, specifically recognize phosphorylated tyrosine residues on other molecules and mediate interactions between SHP2 and these molecules. Biochemical and structural studies indicate that, in the basal state, the N-SH2 domain is wedged into the PTP domain and forms a “backside loop” to prevent substrate accessing. Upon binding of an appropriate phosphotyrosyl (p-Tyr) peptide, N-SH2 alters its conformation and releases the PTP domain from the auto-inhibitory confirmation (2022). In addition, mutagenesis and protease-resistance studies suggest that phosphorylation of Tyr542 and Tyr580 in the C-terminal tail also regulates SHP2 activity. Phosphorylated Tyr542 and Tyr580 could be engaged to the N-SH2 and C-SH2 domains, respectively, in an intramolecular manner to stimulate SHP2 activity (23).
SHP2 plays an essential role in hematopoiesis and lymphopoiesis. Homozygous deletion of Exon 3 of SHP2, including the N-SH2 domain-encoding region (amino acids 46–110) (SHP2Δ/Δ), resulted in embryonic lethality at mid-gestation with a defect in mesodermal patterning (24, 25). In vitro differentiation of SHP2Δ/Δ embryonic stem (ES) cells revealed that loss of SHP2 function caused suppression of ES cell differentiation to erythroid and myeloid progenitors (26). These results suggest a positive role of SHP2 in hematopoietic development. Consistent with the in vitro differentiation data, chimeric mouse analyses showed that no SHP2Δ/Δ ES cell-derived progenitors for erythroid or myeloid lineages were detected in the fetal liver or bone marrow of the chimeric mice generated from SHP2Δ/Δ ES cells. In addition to erythroid and myeloid lineages, SHP2 is also required for lymphoid development. The RAG-2–deficient blastocyst complementation assay showed that no mature T and B cells or even Thy-1 positive or B220 positive precursor lymphocytes derived from the mutant ES cells were detected in the chimeric mice generated from SHP2Δ/Δ ES cells and Rag-2–deficient blastocysts (27). It appears that the blackage of the hematopoietic development of the SHP2 mutant ES cells occurred at a very early stage, since primitive hematopoiesis in the yolk sac of SHP2Δ/Δ embryos was also defective (28). Notably, reintroduction of WT SHP2 into SHP2Δ/Δ ES cells restored both primitive and definitive hematopoietic potential of the mutant ES cells (29), suggesting that the defective hematopoietic development is directly attributable to the loss of SHP2 function and that the defect is cell autonomous.
Consistent with the notion that SHP2 phosphatase plays a positive role in hematopoietic cell development, somatic mutations in SHP2-encoding gene PTPN11 that cause hyperactivation of its catalytic activity have been identified in various childhood leukemias, such as juvenile myelomonocytic leukemia (JMML), B cell acute lymphoblastic leukemia, and acute myeloid leukemia (AML) (3032). SHP2 represents the first identified proto-oncogene that encodes a tyrosine phosphatase (33, 34). The SHP2 disease mutations are located in the N-SH2 and PTP domains and cause changes in the amino acid residues at the interface formed by the two domains in the self-inhibited SHP2 conformation. It is thus thought that the mutations cause a decrease in the affinity of the binding between the N-SH2 and the phosphatase domains, leading to hyperactivation of SHP2 catalytic activity by allowing access to the active site on the enzyme. The SHP2 mutations appear to play a causal role in the development of related diseases, as SHP2 mutations and other well-known JMML-associated Ras or Nf1 mutations are mutually exclusive in the patients (30, 31, 35). Moreover, recent studies have shown that single SHP2 activating mutations are sufficient to induce cytokine hypersensitivity in myeloid progenitor cells and JMML-like myeloproliferative disease in mice (3640).
The molecular mechanisms underlying the positive role of SHP2 phosphatase in hematopoietic cell development and function are not completely understood. Since cytokines play an essential role in the hematopoietic process, SHP2 may promote hematopoiesis through the JAK/STAT pathway that is activated by cytokines. However, the SHP2 function in this pathway is rather complicated. Unlike the promoting role that SHP2 plays in the Ras/Erk and PI3/Akt signaling pathways (20), SHP2 both enhances and inhibits signaling in the JAK/STAT pathway, depending on the acting sites. In addition, different JAK/STAT pathways initiated by different extracellular signals may be differentially regulated by SHP2 phosphatase.
SHP2 negatively regulates JAK/STAT
SHP2 negatively regulates the IFN-induced JAK1/STAT1(2) pathway. INF-γ and INF-α are known to suppress cell viability through the JAK/STAT pathway. In SHP2Δ/Δ mouse fibroblasts, IFN-γ and IFN-α treatment resulted in elevated tyrosine phosphorylation levels of STAT1 and STAT2, and augmented suppression of cell viability. Reintroduction of WT SHP2 protein reversed these effects (41). Specifically, phosphorylation at the tyrosine residue Tyr701 of STAT1 induced by IFN-α was enhanced and prolonged in SHP2Δ/Δ cells (42). Moreover, abolishment of protein kinase C-mediated inhibition of IFN-α signaling was observed in the SHP2 mutant cells (43). Consistent with these observations, purified GST-SHP2 dephosphorylated STAT1 at both tyrosine and serine residues when immunoprecipitated phospho-STAT1 or phosphor-peptides corresponding to the sequence surrounding Tyr701 or Ser727 of STAT1 were used as the substrates (42). These results thus indicate that SHP2 negatively regulates the INF-induced JAK/STAT pathway by dephosphorylating STAT1(2).
SHP2 also interacted with STAT5a in a tyrosine phosphorylation-dependent manner and purified SHP2 protein directly dephosphorylated STAT5 or tyrosine-phosphorylated peptides derived from STAT5 in the in vitro tyrosine phosphatase assay (4446). In agreement with these results, tyrosine-phosphorylated STAT5 associated with a substrate-trapping mutant of SHP2 (SHP2 Cys459Ser) (44, 45). Moreover, overexpression of WT SHP2 in Ba/F3 cells and in primary bone marrow hematopoietic progenitor cells resulted in a decreased phosphorylation level of STAT5 in response to IL-3 stimulation (46). This was largely because STAT5 dephosphorylation was accelerated by overexpression of SHP2 (46), since STAT5 dephosphorylation was markedly delayed in SHP2Δ/Δ cells (44).
In addition, there is also evidence that SHP2 negatively regulates the activity of STAT3, a crucial signaling protein involved in maintaining the self-renewal feature of ES cells and in hematopoietic cell response to the cytokines that function through the gp130 receptor. SHP2Δ/Δ mutant mouse ES cells showed defective differentiation and more efficient self-renewal in the presence of leukemia inhibitory factor (LIF), which was at least in part due to an increased STAT3 activity in the absence of functional SHP2 (29, 47). Similar negative regulation of STAT3 by SHP2 was observed in SHP2-deficient neural cells generated from SHP2 conditional knockout mice (48, 49). In addition to the LIF-induced gp130 signaling pathway, the IL-6-activated gp130 pathway was also inhibited by SHP2. A mutation of the SHP2 binding site (Y759F) in gp130 in the knock-in mice resulted in lymphoadenopathy, splenomegaly, and an enhanced acute-phase immune response (50). Therefore, SHP2 appears to directly inhibit activation of STATs in various pathways. Intriguingly, although SHP2 normally dephosphorylates STAT5, IL3-induced phosphorylation of STAT5 was enhanced rather than decreased in hematopoietic cells harboring SHP2 E76K and D61G leukemia mutations that cause hyperactivation of the SHP2 catalytic activity (38, 40). Further investigations revealed that dephosphorylation of STAT5 by SHP2 E76K was delayed (40). Since overexpression (5-to-6 fold) of WT SHP2 in hematopoietic cells accelerated dephosphorylation of STAT5 and attenuated hematopoietic potential (46), the dampened dephosphorylation activity of SHP2 E76K indicates that the substrate specificity of the mutant SHP2 is altered by the E76K mutation, although the underlying mechanisms remain to be determined.
SHP2 positively regulates JAK/STAT signaling
A large body of data also support that SHP2 promotes JAK/STAT pathways. One of the most compelling evidence is that the activity of STAT5 was suppressed in the SHP2−/− mouse mammary gland cells in SHP2 conditional knockout mice (51). This result suggests a positive role of SHP2 in the prolactin-induced JAK2 activation pathway. JAK2 tends to associate with suppressor of cytokine signaling (Socs)1, which targets JAK2 to a ubiquitin-dependent degradation pathway and serves as a negative regulator for the JAK2/STAT5 pathway. The interaction between JAK2 and Socs1 is mediated by phosphorylation of Tyr1007 in JAK2. In vitro studies demonstrated that SHP2 was able to dephosphorylate this Tyr site and prevent the formation of the JAK2-Socs1 complex and subsequent degradation of Jak2 (52). Upon being released from the inhibitory effects of Socs1, JAK2 is recruited to the prolactin receptor (PrlR) and phosphorylates STAT5 (52). The physical interaction between SHP2 and the JAK2-PrlR complex is required for STAT5 activation and translocation into the nucleus to activate gene expression (52). In addition, it has been shown that SHP2 shares the same binding sites with the signaling suppressor Socs3, owing to similar binding preference of their SH2 domains (53, 54). Thus, it is also possible that SHP2 promotes cytokine signaling by limiting the negative feedback mediated by Socs3 and that this SHP2 function depends on its SH2 domains rather than the catalytic domain. Using catalytically-inactive SHP2 (SHP2 C459S) overexpressing Ba/F3 cells and immortalized SHP2Δ/Δ hematopoietic cells derived from SHP2 knockout embryos, our laboratory showed that SHP2 functioned at multiple sites in the IL-3-induced JAK2/STAT5 signaling in both catalytic-dependent and -independent fashion (55). SHP2 acts immediately downstream of the receptor, facilitating IL3-induced activation of JAK2. In SHP2Δ/Δ cells in which the truncated SHP2 was barely detectable, JAK2 activation was abolished (55). Consequently, phosphorylation of STAT5, the substrate of JAK2 kinase, was impaired in the SHP2 mutant cells (55). It seems that SHP2 functions in JAK2 activation as an adaptor protein. However, further studies showed that the catalytic activity of SHP2 was required for optimal activation of JAK2. JAK2 activation in SHP2 C459S overexpressing cells was decreased. As a result of reduced JAK2 activation, phosphorylation of STAT5 was also decreased (55). Consistent with this notion, expressing catalytically-deficient mutant SHP2 in COS7 cells inhibited the induction of tyrosine phosphorylation and DNA-binding activity of STAT5 upon prolactin stimulation (56). Additionally, the positive role of SHP2 catalytic activity in JAK2 activation is also supported by the recent observation that JAK2 activation in hematopoietic cells harboring the SHP2 activating mutation E76K was enhanced (40).
Collectively, these studies suggest that SHP2 has dual functions in the same JAK2/STAT5 pathway. This may be true, since both a decrease in STAT5 phosphorylation and a delay in STAT5 dephosphorylation (sustained low-level STAT5 phosphorylation) were observed in catalytically-inactive mutant SHP2 overexpressing or SHP2Δ/Δ cells (44, 52, 55, 57). How SHP2 functions at multiple sites in the same pathway, however, remains to be further characterized. SHP2 may first act as a positive regulator for the activation of JAK2 and then inhibits the activated pathway by dephosphorylating STAT5. Alternatively, different fractions of the cytoplasmic SHP2 act at different sites, simultaneously functioning in both catalytic-dependent and –independent fashion.
3.2. Other PTPs
SHP1
SHP1 phosphatase shares a similar overall structure and a high homology with SHP2. However, unlike SHP2 which is ubiquitously expressed, SHP1 is restricted in hematopoietic cells (20). The functions of SHP1 in hematopoietic cells and lymphocytes have been revealed by numerous studies using motheaten mice, which are deficient in SHP1 expression. Motheaten mice display hyperproliferation and abnormal activation of granulocytes and macrophages, and an autoimmunity-like phenotype. These defects are at least in part attributable to the loss of SHP1 as a negative regulator for the JAK/STAT pathway (2, 5861).
SHP1 down regulates erythropoietin (EPO)-induced proliferative signals by binding to the EPO receptor (EPOR) and dephosphorylating the JAK2 associated with EPOR. Cells expressing a mutant EPOR defective in SHP1 binding displayed hypersensitivity to EPO stimulation and prolonged EPO-induced autophosphorylation of JAK2 (62, 63). SHP1 is also involved in the dephosphorylation of JAK1. The IFN-α-induced tyrosine phosphorylation of JAK1 was enhanced in SHP1 deficient macrophages (64). In addition, expression of an inactive SHP1 (R459M) in Ba/F3 cell line increased the proliferative response to IL-3 and cell survival following IL-3 withdrawal (65). The overall level of IL-3-induced tyrosine phosphorylation of STAT5 was reduced upon expression of WT SHP1 and increased when R459M SHP1 was expressed (65).
Consistent with the negative role of SHP1 in the JAK/STAT pathway, silencing of SHP1 by promoter methylation is often associated with various kinds of leukemia and lymphomas, myeloma and acute myeloid leukemia, and the effect caused by SHP1 silencing is at least partially attributed to an increased activities in the JAK/STAT pathway (66). Eighty percent of myeloma samples showed SHP1 hypermethylation, concomitant with a constitutive STAT3 phosphorylation. Reintroduction of SHP1 resulted in barely detectable phosphorylated STAT3, suggesting that STAT3 may also be a substrate of SHP1 (6769). Recently, defective SHP1 expression has also been detected in most cases of ALK positive anaplastic large-cell lymphoma (ALK(+)ALCL) (70). Transfection of SHP1 or induction of SHP1 with an inhibitor of DNA methyltransferase (5-AZA) in ALK(+)ALCL cell line, Karpas 299, caused an attenuated phosphorylation level of JAK3 and STAT3, subsequent down-regulation of STAT3 targets including cyclin D3, mcl-1 and bcl-2, and a significant G1 cell cycle arrest. Co-immunoprecipitation studies showed that SHP1 was physically associated with JAK3. These results suggest that loss of SHP1 contributes to the pathogenesis of ALK(+)ALCL by leaving the phosphorylation and activation of JAK3/STAT3 unchecked (71, 72).
By contrast, SHP1 has been noted to have a positive role in promoting JAK/STAT signaling in some circumstances. For example, the epidermal growth factor (EGF)- and IFN-γ-induced STAT activation was suppressed by expressing a catalytically-inactive form of SHP1 in HeLa cells, while this pathway was essentially unaffected by the expression of WT SHP1 (73). The precise mechanism of how this molecule achieves opposing functions in different systems remains to be clarified.
CD45, PTP1B, TC-PTP, PTPRT, and PTP-BL
CD45 is a receptor tyrosine phosphatase highly expressed by hematopoietic cells. It plays an important role in controlling antigen-receptor signaling in T and B cells (74, 75). CD45 is shown to be able to dephosphorylate all JAKs in murine cells (76), and dephosphorylate JAK1 and JAK3 in human cells (77). CD45 deficient cells experienced prolonged JAK/STAT activation in response to IL-7 stimulation. The removal of CD45 also increased the erythroid colony formation and antiviral activity, which is consistent with the idea that CD45 negatively regulates EPO and IFN signaling by dephosphorylating JAKs (76, 78). However, the physiological significance of the role of CD45 in controlling the JAK/STAT pathways still needs to be further determined.
PTP1B and TC-PTP are two highly related PTPs, sharing great similarities in the catalytic domains. While PTP1B is expressed in many tissues, TC-PTP is mainly in hematopoietic cells (79). PTP1B binds phosphorylated JAK1 upon leptin and IFN-γ treatment, and is implicated in the negative regulation of these signaling pathways. Increased phosphorylation of JAK2, STAT3, and STAT5 has been observed in PTP1B deficient embryonic fibroblasts (8083). TC-PTP can also target JAK1, JAK3, STAT1, STAT3 and STAT5. Phosphorylation of JAK1 and STAT1 is enhanced in TC-PTP knockout cells (8486).
More recently, it has been shown that PTPRT, a receptor-type tyrosine phosphatase, also dephosphorylates STAT3 at Tyr705, an essential tyrosine residue for the function of STAT3 (87). Accordingly, overexpression of PTPRT reduces the expression of STAT3 target genes. In addition, PTP-Basophil like (PTP-BL), a large non-transmembrane PTP, has been shown to dephosphorylate STAT proteins both in vitro and in vivo, and has been identified as a STAT PTP. In CD4 positive T cells, PTP-BL deficiency led to increased and prolonged activation of STAT4 and STAT6, and consequently enhanced Th1 and Th2 cell differentiation (88).
In summary, many PTPs participate in the regulation of the JAK/STAT signaling pathway and different PTPs recognize specific substrates. The role of PTPs in the JAK/STAT pathway has important implications in physiology and diseases. Nevertheless, many issues regarding the biochemical bases of the interactions of PTPs with the JAK/STAT pathway still remain to be resolved. Some prominent questions are: Why do some phosphatases, in particular, SHP2 promote local signaling? What is the direct biochemical significance of their phosphatase activities? Since several phosphatases dephosphorylate the same targets, how are functions of PTPs coordinated temporally and spatially? Addressing these questions will lead to a better understanding of how JAK/STAT signaling is modulated and why malfunction of this pathway results in hematopoietic and immune disorders. The information gathered may also lead to rational design of new therapeutics for treatment of the relevant diseases.
Acknowledgments
The authors apologize to many colleagues whose contributions were omitted from this review due to limited space. This work was supported by National Institutes of Health grants (HL068212 and HL082670 to C.K.Q.).
Abbreviations
JAKJanus kinase
STATsignal transducer and activator of transcription
PTPProtein tyrosine phosphatase
IFNInterferon
SH2Src homoglogy 2
ES cellsembryonic stem cells
SocsSuppressor of cytokine signaling

1. Darnell JE, Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;26:1415–1421. [PubMed]
2. Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol. 2003;3:900–911. [PubMed]
3. Qu CK. Role of the SHP-2 tyrosine phosphatase in cytokine-induced signaling and cellular response. Biochim Biophys Acta. 2002;159:297–301. [PubMed]
4. Tonks NK, Neel BG. Combinatorial control of the specificity of protein tyrosine phosphatases. Curr Opin Cell Biol. 2001;13:182–195. [PubMed]
5. Darnell JE., Jr STATs and gene regulation. Science. 1997;277:1630–1635. [PubMed]
6. Levy DE, Darnell JE., Jr Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3:651–662. [PubMed]
7. Shuai K, Stark GR, Kerr IM, Darnell JE., Jr A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science. 1993;261:1744–1746. [PubMed]
8. Muller M, Laxton C, Briscoe J, Schindler C, Improta T, Darnell JE, Jr, Stark GR, Kerr IM. Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon-alpha and -gamma signal transduction pathways. Embo J. 1993;12:4221–4228. [PubMed]
9. Fu XY, Zhang JJ. Transcription factor p91 interacts with the epidermal growth factor receptor and mediates activation of the c-fos gene promoter. Cell. 1993;74:1135–1145. [PubMed]
10. Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE., Jr Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell. 1994;76:821–828. [PubMed]
11. Xu X, Sun YL, Hoey T. Cooperative DNA binding and sequence-selective recognition conferred by the STAT amino-terminal domain. Science. 1996;273:794–797. [PubMed]
12. Shuai K, Liao J, Song MM. Enhancement of antiproliferative activity of gamma interferon by the specific inhibition of tyrosine dephosphorylation of Stat1. Mol Cell Biol. 1996;16:4932–4941. [PMC free article] [PubMed]
13. Yamaoka K, Saharinen P, Pesu M, Holt VE, 3rd, Silvennoinen O, O’Shea JJ. The Janus kinases (Jaks) Genome Biol. 2004;5:253. [PMC free article] [PubMed]
14. Schindler C, Levy DE, Decker T. JAK-STAT signaling: from interferons to cytokines. J Biol Chem. 2007;282:20059–20063. [PubMed]
15. O’Shea JJ, Gadina M, Schreiber RD. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell. 2002;109:S121–S131. [PubMed]
16. Freeman RM, Jr, Plutzky J, Neel BG. Identification of a human src homology 2-containing protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew. Proc Natl Acad Sci U S A. 1992;89:11239–11243. [PubMed]
17. Ahmad S, Banville D, Zhao Z, Fischer EH, Shen SH. A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains. Proc Natl Acad Sci U S A. 1993;90:2197–2201. [PubMed]
18. Vogel W, Lammers R, Huang J, Ullrich A. Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. Science. 1993;259:1611–1614. [PubMed]
19. Feng GS, Hui CC, Pawson T. SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science. 1993;259:1607–1611. [PubMed]
20. Neel BG, Gu H, Pao L. The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003;28:284–293. [PubMed]
21. Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998;92:441–450. [PubMed]
22. Barford D, Neel GB. Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2. Structure. 1998;6:249–254. [PubMed]
23. Lu W, Gong D, Bar-Sagi D, Cole AP. Site-specific incorporation of a phosphotyrosine mimetic reveals a role for tyrosine phosphorylation of SHP-2 in cell signaling. Mol Cell. 2001;8:759–769. [PubMed]
24. Arrandale JM, Gore-Willse A, Rocks S, Ren JM, Zhu J, Davis A, Livingston JN, Rabin UD. Insulin signaling in mice expressing reduced levels of Syp. J Biol Chem. 1996;271:21353–21358. [PubMed]
25. Saxton TM, Henkemeyer M, Gasca S, Shen R, Rossi DJ, Shalaby F, Feng GS, Pawson T. Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. Embo J. 1996;16:2352–2364. [PubMed]
26. Qu CK, Shi ZQ, Shen R, Tsai FY, Orkin SH, Feng SG. A deletion mutation in the SH2-N domain of Shp-2 severely suppresses hematopoietic cell development. Mol Cell Biol. 1997;17:5499–5507. [PMC free article] [PubMed]
27. Qu CK, Nguyen S, Chen J, Feng SG. Requirement of Shp-2 tyrosine phosphatase in lymphoid and hematopoietic cell development. Blood. 2001;97:911–914. [PubMed]
28. Qu CK, Yu WM, Azzarelli B, Cooper S, Broxmeyer HE, Feng SG. Biased suppression of hematopoiesis and multiple developmental defects in chimeric mice containing Shp-2 mutant cells. Mol Cell Biol. 1998;18:6075–6082. [PMC free article] [PubMed]
29. Chan RJ, Johnson SA, Li Y, Yoder MC, Feng GS. A definitive role of Shp-2 tyrosine phosphatase in mediating embryonic stem cell differentiation and hematopoiesis. Blood. 2003;102:2074–2080. [PubMed]
30. Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb DB. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003;34:148–150. [PubMed]
31. Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH, Cheng JW, Lee CM, Stokoe D, Bonifas JM, Curtiss NP, Gotlib J, Meshinchi S, Le Beau MM, Emanuel PD, Shannon MK. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood. 2004;103:2325–2331. [PubMed]
32. Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M, Palmi C, Carta C, Pession A, Arico M, Masera G, Basso G, Sorcini M, Gelb BD, Biondi A. Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood. 2004;104:307–313. [PubMed]
33. Chan RJ, Feng SG. PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood. 2007;109:862–867. [PubMed]
34. Mohi MG, Neel GB. The role of Shp2 (PTPN11) in cancer. Curr Opin Genet Dev. 2007;17:23–30. [PubMed]
35. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb DB. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29:465–468. [PubMed]
36. Araki T, Mohi MG, Ismat FA, Bronson RT, Williams IR, Kutok JL, Yang W, Pao LI, Gilliland DG, Epstein JA, Neel BG. Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nat Med. 2004;10:849–857. [PubMed]
37. Chan RJ, Leedy MB, Munugalavadla V, Voorhorst CS, Li Y, Yu M, Kapur R. Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Blood. 2005;105:3737–3742. [PubMed]
38. Mohi MG, Williams IR, Dearolf CR, Chan G, Kutok JL, Cohen S, Morgan K, Boulton C, Shigematsu H, Keilhack H, Akashi K, Gilliland DG, Neel BG. Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer Cell. 2005;7:179–191. [PubMed]
39. Schubbert S, Lieuw K, Rowe SL, Lee CM, Li X, Loh ML, Clapp DW, Shannon MK. Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells. Blood. 2005;106:311–317. [PubMed]
40. Yu WM, Daino H, Chen J, Bunting KD, Qu CK. Effects of a leukemia-associated gain-of-function mutation of SHP-2 phosphatase on interleukin-3 signaling. J Biol Chem. 2006;281:5426–5434. [PubMed]
41. You M, Yu DH, Feng GS. Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway. Mol Cell Biol. 1999;19:2416–2424. [PMC free article] [PubMed]
42. Wu TR, Hong YK, Wang XD, Ling MY, Dragoi AM, Chung AS, Campbell AG, Han ZY, Feng GS, Chin EY. SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei. J Biol Chem. 2002;277:47572–47580. [PubMed]
43. Du Z, Shen Y, Yang W, Mecklenbrauker I, Neel BG, Ivashkiv BL. Inhibition of IFN-alpha signaling by a PKC- and protein tyrosine phosphatase SHP-2-dependent pathway. Proc Natl Acad Sci U S A. 2005;102:10267–10272. [PubMed]
44. Chen Y, Wen R, Yang S, Schuman J, Zhang EE, Yi T, Feng GS, Wang D. Identification of Shp-2 as a Stat5A phosphatase. J Biol Chem. 2003;278:16520–16527. [PubMed]
45. Yu CL, Jin YJ, Burakoff SJ. Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation. J Biol Chem. 2000;275:599–604. [PubMed]
46. Chen J, Yu WM, Bunting KD, Qu KC. A negative role of SHP-2 tyrosine phosphatase in growth factor-dependent hematopoietic cell survival. Oncogene. 2004;23:3659–3669. [PubMed]
47. Qu CK, Feng SG. Shp-2 has a positive regulatory role in ES cell differentiation and proliferation. Oncogene. 1998;17:433–439. [PubMed]
48. Zhang EE, Chapeau E, Hagihara K, Feng SG. Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc Natl Acad Sci U S A. 2004;101:16064–16069. [PubMed]
49. Ke Y, Zhang EE, Hagihara K, Wu D, Pang Y, Klein R, Curran T, Ranscht B, Feng GS. Deletion of Shp2 in the Brain Leads to Defective Proliferation and Differentiation in Neural Stem Cells and Early Postnatal Lethality. Mol Cell Biol. 2007;27:6706–6717. [PMC free article] [PubMed]
50. Ohtani T, Ishihara K, Atsumi T, Nishida K, Kaneko Y, Miyata T, Itoh S, Narimatsu M, Maeda H, Fukada T, Itoh M, Okano H, Hibi M, Hirano T. Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3- and SHP2-mediated signals in immune responses. Immunity. 2000;12:95–105. [PubMed]
51. Ke Y, Lesperance J, Zhang EE, Bard-Chapeau EA, Oshima RG, Muller WJ, Feng GS. Conditional deletion of Shp2 in the mammary gland leads to impaired lobulo-alveolar outgrowth and attenuated Stat5 activation. J Biol Chem. 2006;281:34374–34380. [PMC free article] [PubMed]
52. Ali S, Nouhi Z, Chughtai N, Ali S. SHP-2 regulates SOCS-1-mediated Janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor. J Biol Chem. 2003;278:52021–52031. [PubMed]
53. Nicholson SE, De Souza D, Fabri LJ, Corbin J, Willson TA, Zhang JG, Silva A, Asimakis M, Farley A, Nash AD, Metcalf D, Hilton DJ, Nicola NA, Baca M. Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. Proc Natl Acad Sci U S A. 2000;97:6493–6498. [PubMed]
54. De Souza D, Fabri LJ, Nash A, Hilton DJ, Nicola NA, Baca M. SH2 domains from suppressor of cytokine signaling-3 and protein tyrosine phosphatase SHP-2 have similar binding specificities. Biochemistry. 2002;41:9229–9236. [PubMed]
55. Yu WM, Hawley TS, Hawley RG, Qu KC. Catalytic-dependent and -independent roles of SHP-2 tyrosine phosphatase in interleukin-3 signaling. Oncogene. 2003;22:5995–6004. [PubMed]
56. Berchtold S, Volarevic S, Moriggl R, Mercep M, Groner B. Dominant negative variants of the SHP-2 tyrosine phosphatase inhibit prolactin activation of Jak2 (janus kinase 2) and induction of Stat5 (signal transducer and activator of transcription 5)-dependent transcription. Mol Endocrinol. 1998;12:556–567. [PubMed]
57. Ali S, Chen Z, Lebrun JJ, Vogel W, Kharitonenkov A, Kelly PA, Ullrich A. PTP1D is a positive regulator of the prolactin signal leading to beta-casein promoter activation. Embo J. 1996;15:135–142. [PubMed]
58. Shultz LD, Schweitzer PA, Rajan TV, Yi T, Ihle JN, Matthews RJ, Thomas ML, Beier RD. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell. 1993;73:1445–1454. [PubMed]
59. Tsui HW, Siminovitch KA, de Souza L, Tsui WF. Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nat Genet. 1993;4:124–129. [PubMed]
60. Starr R, Hilton JD. Negative regulation of the JAK/STAT pathway. Bioessays. 1999;21:47–52. [PubMed]
61. Valentino L, Pierre J. JAK/STAT signal transduction: regulators and implication in hematological malignancies. Biochem Pharmacol. 2006;71:713–721. [PubMed]
62. Klingmuller U, Lorenz U, Cantley LC, Neel BG, Lodish HF. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell. 1995;80:729–738. [PubMed]
63. Jiao H, Berrada K, Yang W, Tabrizi M, Platanias LC, Yi T. Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1. Mol Cell Biol. 1996;16:6985–6992. [PMC free article] [PubMed]
64. David M, Chen HE, Goelz S, Larner AC, Neel BG. Differential regulation of the alpha/beta interferon-stimulated Jak/Stat pathway by the SH2 domain-containing tyrosine phosphatase SHPTP1. Mol Cell Biol. 1995;15:7050–7058. [PMC free article] [PubMed]
65. Paling NR, Welham JM. Role of the protein tyrosine phosphatase SHP-1 (Src homology phosphatase-1) in the regulation of interleukin-3-induced survival, proliferation and signalling. Biochem J. 2002;368:885–894. [PubMed]
66. Johan MF, Bowen DT, Frew ME, Goodeve AC, Reilly JT. Aberrant methylation of the negative regulators RASSFIA, SHP-1 and SOCS-1 in myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol. 2005;129:60–65. [PubMed]
67. Oka T, Ouchida M, Koyama M, Ogama Y, Takada S, Nakatani Y, Tanaka T, Yoshino T, Hayashi K, Ohara N, Kondo E, Takahashi K, Tsuchiyama J, Tanimoto M, Shimizu K, Akagi T. Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res. 2002;62:6390–6394. [PubMed]
68. Chim CS, Fung TK, Cheung WC, Liang R, Kwong YL. SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Blood. 2004;103:4630–4635. [PubMed]
69. Zhang Q, Wang HY, Marzec M, Raghunath PN, Nagasawa T, Wasik AM. STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc Natl Acad Sci U S A. 2005;102:6948–6953. [PubMed]
70. Khoury JD, Rassidakis GZ, Medeiros LJ, Amin HM, Lai R. Methylation of SHP1 gene and loss of SHP1 protein expression are frequent in systemic anaplastic large cell lymphoma. Blood. 2004;104:1580–1581. [PubMed]
71. Han Y, Amin HM, Franko B, Frantz C, Shi X, Lai R. Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma. Blood. 2006;108:2796–2803. [PubMed]
72. Han Y, Amin HM, Frantz C, Franko B, Lee J, Lin Q, Lai R. Restoration of shp1 expression by 5-AZA-2′-deoxycytidine is associated with downregulation of JAK3/STAT3 signaling in ALK-positive anaplastic large cell lymphoma. Leukemia. 2006;20:1602–1609. [PubMed]
73. You M, Zhao Z. Positive effects of SH2 domain-containing tyrosine phosphatase SHP-1 on epidermal growth factor- and interferon-gamma-stimulated activation of STAT transcription factors in HeLa cells. J Biol Chem. 1997;272:23376–23381. [PubMed]
74. Penninger JM, Irie-Sasaki J, Sasaki T, Oliveira-dos-Santos AJ. CD45: new jobs for an old acquaintance. Nat Immunol. 2001;2:389–396. [PubMed]
75. Hermiston ML, Xu Z, Weiss A. CD45: a critical regulator of signaling thresholds in immune cells. Annu Rev Immunol. 2003;21:107–137. [PubMed]
76. Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G, Griffiths E, Krawczyk C, Richardson CD, Aitken K, Iscove N, Koretzky G, Johnson P, Liu P, Rothstein DM, Penninger MJ. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature. 2001;409:349–354. [PubMed]
77. Yamada T, Zhu D, Saxon A, Zhang K. CD45 controls interleukin-4-mediated IgE class switch recombination in human B cells through its function as a Janus kinase phosphatase. J Biol Chem. 2002;277:28830–28835. [PubMed]
78. Fleming HE, Milne CD, Paige CJ. CD45-deficient mice accumulate Pro-B cells both in vivo and in vitro. J Immunol. 2004;173:2542–2551. [PubMed]
79. Neel BG, Tonks KN. Protein tyrosine phosphatases in signal transduction. Curr Opin Cell Biol. 1997;9:193–204. [PubMed]
80. Myers MP, Andersen JN, Cheng A, Tremblay ML, Horvath CM, Parisien JP, Salmeen A, Barford D, Tonks NK. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J Biol Chem. 2001;276:47771–47774. [PubMed]
81. Cheng A, Uetani N, Simoncic PD, Chaubey VP, Lee-Loy A, McGlade CJ, Kennedy BP, Tremblay LM. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev Cell. 2002;2:497–503. [PubMed]
82. Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, Kim YB, Elmquist JK, Tartaglia LA, Kahn BB, Neel BG. PTP1B regulates leptin signal transduction in vivo. Dev Cell. 2002;2:489–495. [PubMed]
83. Gu F, Dube N, Kim JW, Cheng A, Ibarra-Sanchez Mde J, Tremblay ML, Boisclair YR. Protein tyrosine phosphatase 1B attenuates growth hormone-mediated JAK2-STAT signaling. Mol Cell Biol. 2003;23:3753–3762. [PMC free article] [PubMed]
84. ten Hoeve J, de Jesus Ibarra-Sanchez M, Fu Y, Zhu W, Tremblay M, David M, Shuai K. Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol Cell Biol. 2002;22:5662–5668. [PMC free article] [PubMed]
85. Simoncic PD, Lee-Loy A, Barber DL, Tremblay ML, McGlade CJ. The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3. Curr Biol. 2002;12:446–453. [PubMed]
86. Bourdeau A, Dube N, Heinonen KM, Theberge JF, Doody KM, Tremblay LM. TC-PTP-deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-{gamma} Blood. 2007;109:4220–4228. [PubMed]
87. Zhang X, Guo A, Yu J, Possemato A, Chen Y, Zheng W, Polakiewicz RD, Kinzler KW, Vogelstein B, Velculescu VE, Wang ZJ. Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T. Proc Natl Acad Sci U S A. 2007;104:4060–4964. [PubMed]
88. Nakahira M, Tanaka T, Robson BE, Mizgerd JP, Grusby MJ. Regulation of signal transducer and activator of transcription signaling by the tyrosine phosphatase PTP-BL. Immunity. 2007;26:163–176. [PubMed]