2013
DOI: 10.4049/jimmunol.1203118
|View full text |Cite
|
Sign up to set email alerts
|

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

Abstract: Tyk2 belongs to the Janus protein tyrosine kinase family and is involved in signaling of immunoregulatory cytokines (type I and III IFNs, IL-6, IL-10, and IL-12 families) via its interaction with shared receptor subunits. Depending on the receptor complex, Tyk2 is coactivated with either Jak1 or Jak2, but a detailed molecular characterization of the interplay between the two enzymes is missing. In human populations, the Tyk2 gene presents high levels of genetic diversity with >100 nonsynonymous variants… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
1
1
1
1

Citation Types

10
77
1

Year Published

2013
2013
2023
2023

Publication Types

Select...
7
2

Relationship

0
9

Authors

Journals

citations
Cited by 63 publications
(88 citation statements)
references
References 57 publications
10
77
1
Order By: Relevance
“…Random mutagenesis approaches identified mutations in TYK2 JH2 that abrogate the intrinsic catalytic activity and formation of the high-affinity IFN type I receptor (27). A similar phenotype is also observed in the autoimmune disease-linked I684S variant of TYK2 (28).…”
Section: The Atomic Coordinates and Structure Factors (Codes 5c03 Andmentioning
confidence: 81%
“…Random mutagenesis approaches identified mutations in TYK2 JH2 that abrogate the intrinsic catalytic activity and formation of the high-affinity IFN type I receptor (27). A similar phenotype is also observed in the autoimmune disease-linked I684S variant of TYK2 (28).…”
Section: The Atomic Coordinates and Structure Factors (Codes 5c03 Andmentioning
confidence: 81%
“…A scaffold function for TYK2 has previously been demonstrated for type I IFN and IL-10Rs in human cell lines, where full-length TYK2 protein was required, but the catalytic activity of TYK2 was dispensable for cell-surface receptor expression (11). In addition, a study of two rare disease-associated human TYK2 variants found that although these variants lack catalytic activity, STAT protein phosphorylation downstream of IL-6, IFN-a, and IL-10 signaling is intact in a human cell line reconstituted with the mutant TYK2 proteins and in EBVtransformed B cells from patients harboring the mutant TYK2 proteins (16). In contrast, a study of mice engineered to express a catalytically inactive TYK2 protein found impaired IFN-a signaling similar to that of TYK2-deficient mice; however, this was likely a consequence of a significant reduction in the total level of TYK2 protein in these mice (17).…”
Section: Discussionmentioning
confidence: 99%
“…In this regard, it has been suggested that TYK2 plays a similar role in the surface expression of the human IL-10R (11). The overall contribution of TYK2 catalytic activity to cytokine responses is still poorly understood, although a few studies have assessed the role of TYK2 catalytic activity in IFN signaling by reconstituting TYK2-deficient cell lines with mutant versions of TYK2 (12)(13)(14)(15)(16) or by generating mice that express a catalytically inactive TYK2 protein (17).…”
mentioning
confidence: 99%
“…40 However, in line with our data, noncatalytic functions of human Jak1 and Tyk2 in the context of IFNAR1, IL-6, and IL-10 stimulation were reported, suggesting that 1 catalytically competent Jak is sufficient for signaling provided that its partner behaves as scaffold, even if inactive. 41,42 Investigation of a Jak3 activation-loop-defective mutant, YY1980/981FF, demonstrates that activation-loop tyrosines are not absolutely required for Jak3 catalytic function, whereas lysine mutation (K885A) in the ATP-binding pocket completely abrogates catalytic activity. 43 Moreover, Jak3-K885A exhibits no kinase-independent function.…”
Section: /2mentioning
confidence: 99%