Differential Regulation of the Alpha/Beta Interferon-Stimulated Jak/Stat Pathway by the SH2 Domain-Containing Tyrosine Phosphatase SHPTP1

Abstract

Interferons (IFNs) induce early-response genes by stimulating Janus family (Jak) tyrosine kinases, leading to tyrosine phosphorylation of Stat transcription factors. Previous studies implicated protein-tyrosine phosphatase (PTP) activity in the control of IFN-regulated Jak/Stat signaling, but the specific PTPs responsible remained unidentified. We have found that SH2 domain-containing PTP1 (SHPTP1; also called PTP1C, HCP, or SHP) reversibly associates with the IFN-␣ receptor complex upon IFN addition. Compared with macrophages from normal littermate controls, macrophages from motheaten mice, which lack SHPTP1, show dramatically increased Jak1 and Stat1␣ tyrosine phosphorylation, whereas Tyk2 and Stat2 activation is largely unaffected. These findings correlate with selectively increased complex formation on a gamma response element, but not an IFN-stimulated response element, in motheaten macrophages. Our results establish that SHPTP1 selectively regulates distinct components of Jak/Stat signal transduction pathways in vivo.Interferons (IFNs) were the first of many cytokines and growth factors that were found to stimulate the expression of early-response genes by inducing the tyrosine phosphorylation of SH2 domain-containing transcription factors (subsequently termed Stats) (20, 21). Tyrosine phosphorylation of Stat proteins induces them to form homodimeric and/or heterodimeric complexes, which translocate to the nucleus and interact with similar elements in a variety of enhancers to promote transcription. Janus family protein-tyrosine kinases (PTKs) are integral components of the signaling cascades regulated by cytokines that activate Stats (17).Recent work in many laboratories has identified several downstream components of IFN-␣/␤ signaling. Two subunits (␣ and ␤) of the IFN-␣/␤ receptor (IFN␣/␤R) have been molecularly cloned (28,44). Binding of IFN-␣/␤ to its receptor results in rapid activation of the Janus PTKs Jak1 and Tyk2. This results in tyrosyl phosphorylation of both Stat1␣ (p91) and Stat2 (p113) and the formation of at least two transcription factor complexes. One complex, composed of a heterotrimer of Stat1␣, Stat2, and the DNA-binding component p48, binds to IFN-stimulated response elements (ISREs) (12,13,30

The SH2 Domain-containing Tyrosine Phosphatase PTP1D Is Required for Interferon α/β-induced Gene Expression

“…Evidence from both in vitro and in vivo studies indicated that tyrosine phosphatases can act as positive as well as negative regulators of the IFN␣/␤-induced Jak/Stat pathway (17,21,22). Recently, we were able to demonstrate that the SH2 domain containing tyrosine phosphatase PTP1C (SHPTP1, HCP, or SHP) functions as a suppressor of IFN␣/␤ signal transduction in hematopoietic cells by specific down-modulation of Jak1 tyrosine phosphorylation (23). Studies of Stat activation by IFN␣/␤ in cell homogenates provided evidence that a tyrosine phosphatase is also required to initiate signal transduction (17).…”

Involvement of Proteasomes in Regulating Jak-STAT Pathways upon Interleukin-2 Stimulation

“…Based on the observation that there is a good correlation between tyrosine dephosphorylation and inactivation of both Jak and STAT proteins, the roles of protein-tyrosine phosphatases in down-regulating the Jak-STAT pathways have been suggested. Indeed, there is genetic and biochemical evidence indicating that protein-tyrosine phosphatases are critical in regulating distinct Jak kinases within specific cytokine receptor complexes (13)(14)(15). The evidence for the involvement of specific protein-tyrosine phosphatases in dephosphorylating STAT proteins, however, is more indirect (16 -18).…”

Reduced Tyk2/SHP-1 interaction and lack of SHP-1 mutation in a kindred of familial hemophagocytic lymphohistiocytosis

“…Moreover, Jak kinases in macrophages from motheaten mice were found to be hyperphosphorylated following IFN␣/␤ treatment. 24 Our recent study demonstrates that SHP-1 directly binds to the Jak family kinases via a region in its N-terminus independently of SH2/phosphotyrosine interactions. 36 As this interaction leads to SHP-1 activation and the dephosphorylation of Jak kinases, it may be a critical factor required for specific and efficient dephosphorylation of SHP-1 substrates.…”

“…This association leads to the activation of SHP-1 PTPase 19,20 and the down-regulation of signaling by the dephosphorylation of substrates. A number of membrane molecules have been found to associate with SHP-1 via its SH2 domains, including receptors of hematopoietic growth factors and cytokines, [21][22][23][24][25] subunits of the B cell antigen receptors [26][27][28][29] and the inhibitory receptor of natural killer cells. 30 The functional significance of these associations is underscored by the increased signaling from these membrane molecules in motheaten hematopoietic cells which lack functional SHP-1.…”

“…30 The functional significance of these associations is underscored by the increased signaling from these membrane molecules in motheaten hematopoietic cells which lack functional SHP-1. 24,28,[31][32][33][34] It is believed that the increased signaling due to loss of the negative regulatory SHP-1 leads to hyperproliferation and organ infiltration of hematopoietic cells in these mice.…”