Association of the Interferon-dependent Tyrosine Kinase Tyk-2 with the Hematopoietic Cell Phosphatase

Yetter, Andrew; Uddin, Shahab; Krolewski, John J.; Jiao, Huaiyuan; Yi, Taolin; Platanias, Leonidas C.

doi:10.1074/jbc.270.31.18179

Cited by 114 publications

(77 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To determine whether such associations are defective in FHLH, we immunoprecipitated SHP-1 from PBMC of the patient and the parents, and probed the immunocomplexes with antibodies against the Jak kinases. Consistent with our previous reports, 36,41 Tyk2 was detected in the SHP-1 immunocomplexes from the father (Figure 4a, lane 2). However, the levels of Tyk2 in the SHP-1 immunocomplexes from the patient and the mother were markedly reduced, representing approximately 5-10% of the father's.…”

Section: Pbmc Of Fhlh Patients Express Normal Levels Of Functional Shsupporting

confidence: 93%

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

et al. 1998

View full text Add to dashboard Cite

Familial hemophagocytic lymphohistiocytosis (FHLH) is an autosomal recessive disease with features similar to those of the murine motheaten phenotype resulting from mutations of protein tyrosine phosphatase SHP-1. This has raised the possibility that defects in SHP-1 or SHP-1-regulated signaling molecules may be present in FHLH. In this study, we examined SHP-1 protein and transcript in the peripheral blood mononuclear cells (PBMC) of an FHLH family. Our results show that the FHLH patient and the parents express comparable levels of a single SHP-1 protein and that the SHP-1 cDNA clone from the patient contains no mutation in the coding region. Interestingly, a reduced association of SHP-1 with the Jak family kinase Tyk2 was detected in the patient and the defect appears to have been inherited from one of the parents. This reduced SHP-1/Tyk2 association is likely due to a defect in Tyk2 or in cellular factors regulating Tyk2, because we found no abnormalities in SHP-1 or in SHP-1 association with the other Jak kinases. These data demonstrate that the SHP-1 gene is intact in FHLH and that the defect in some cases with this disease may involve signaling molecules regulated by SHP-1.

show abstract

Section: Pbmc Of Fhlh Patients Express Normal Levels Of Functional Shsupporting

confidence: 93%

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

et al. 1998

View full text Add to dashboard Cite

show abstract

“…KL may provide an interaction surface for a tyrosine phosphatase that maintains the protein in a low phosphorylated state (32,33). Alternatively, the structural alteration of KL may have repercussions on the conformation of other regions of the protein, leading to the increased accessibility of target tyrosines.…”

Section: Discussionmentioning

confidence: 99%

A dual role for the kinase-like domain of the tyrosine kinase Tyk2 in interferon-α signaling

Yeh

Dondi

Uzé

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Tyrosine kinases of the Janus kinase family initiate cellular responses through their association with receptors for ␣-helical cytokines. In addition to a tyrosine kinase domain, these enzymes possess a kinase-like (KL) domain, whose function remains elusive. To investigate the role of the KL domain of Tyk2 in interferon-␣͞␤ signaling, we transfected a library of Tyk2 cDNAs containing random point mutations in KL into Tyk2-negative cells and selected for loss-of-function Tyk2 mutants. Four such mutants, V584D, G596V, H669P, and R856G, were identified through this screen. Like the wild-type Tyk2, the mutant proteins were able to sustain the level of IFNAR1 receptor protein. However, all four mutants were incapable of restoring high-affinity interferon-␣ binding in Tyk2-negative cells and were also catalytically impaired, even when transiently overexpressed. Interferon-␣ induced phosphorylation, and gene expression could be detected in V584D-or G596V-expressing cells, but not in H669P-or R856G-expressing cells. Furthermore, H669P and R856G proteins were constitutively highly phosphorylated. All together, our findings demonstrate that an intact KL domain is essential for the intrinsic catalytic activity of Tyk2 and for the establishment of a high-affinity interferon-␣ receptor complex.I n mammals, the four Janus kinases (JAKs) (Tyk2, JAK1, JAK2, and JAK3) have been shown to participate in the early steps of signaling cascades originating from cell surface receptors engaged with ␣-helix-bundled cytokine ligands (1-3). One major pathway triggered by these cytokines involves the catalytic activation of the receptor-associated JAK proteins, tyrosine phosphorylation of the cytoplasmic regions of the receptors, recruitment of SH2-containing signal transducers and activators of transcription (STAT) proteins onto the phosphorylated motifs, and phosphorylation of these transcription factors. Activated STATs then translocate into the nucleus and induce the transcription of target genes (1,4,5). Little is known about the molecular mechanisms regulating the JAK enzymes that play a critical role in this signaling pathway.Sequence alignment of the JAKs reveals seven regions of homology, called JH1 to JH7. The amino-terminal region comprises JH3 through JH7 and has been implicated in receptor interaction and stability (3). JH1, located at the carboxyl terminus, is a tyrosine kinase (TK) domain that contains an activation loop, the phosphorylation of which is required for catalytic activation (6-9). The centrally located JH2 or kinase-like (KL) domain exhibits high sequence identity (up to 30%) with kinase domains but lacks intrinsic catalytic activity. Differences between the KL domain and canonical kinase domains are evident in conserved sequences defining the ATP-and substrate-binding cleft, including the glycine-rich loop; the HRDL motif, which is HGNV in KL; and the DFG motif, which is DPG (10). No tyrosine residues are present in the segment of KL corresponding to the activation loop of active kinase domains.Functional conse...

show abstract

“…[36][37][38][39][40][41] Recruitment of SHP-1 in this manner facilitates the down-modulation of tyrosine phosphorylation and mitogenic signaling from the respective receptors. 36,[39][40][41] However, other studies have shown that SHP-1 can also interact directly with members of the Jak kinase family, including Tyk2 and Jak2, to modulate both their tyrosine phosphorylation and activity, 42,43 or to STAT proteins themselves. 44 Myeloid 32D cells have provided a useful model for studying the regulation of granulocytic development.…”

Section: Introductionmentioning

confidence: 99%

The SH2 domain-containing protein tyrosine phosphatase SHP-1 is induced by granulocyte colony-stimulating factor (G-CSF) and modulates signaling from the G-CSF receptor

et al. 2000

View full text Add to dashboard Cite

show abstract

Association of the Interferon-dependent Tyrosine Kinase Tyk-2 with the Hematopoietic Cell Phosphatase

Cited by 114 publications

References 31 publications

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

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

A dual role for the kinase-like domain of the tyrosine kinase Tyk2 in interferon-α signaling

The SH2 domain-containing protein tyrosine phosphatase SHP-1 is induced by granulocyte colony-stimulating factor (G-CSF) and modulates signaling from the G-CSF receptor

Contact Info

Product

Resources

About