Tyrosine Kinase SYK Licenses MyD88 Adaptor Protein to Instigate IL-1α-Mediated Inflammatory Disease

Gurung, Prajwal, Fan, Gaofeng, Lukens, John R., Vogel, Peter, Tonks, Nicholas K., Kanneganti, Thirumala-Devi (April 2017) Tyrosine Kinase SYK Licenses MyD88 Adaptor Protein to Instigate IL-1α-Mediated Inflammatory Disease. Immunity, 46 (4). pp. 635-648. ISSN 1074-7613

URL: https://www.ncbi.nlm.nih.gov/pubmed/28410990
DOI: 10.1016/j.immuni.2017.03.014

Abstract

Summary Mice carrying a hypomorphic point mutation in the Ptpn6 gene (Ptpn6spin mice) develop an inflammatory skin disease that resembles neutrophilic dermatosis in humans. Here, we demonstrated that interleukin-1α (IL-1α) signaling through IL-1R and MyD88 in both stromal and immune cells drive inflammation in Ptpn6spin mice. We further identified SYK as a critical kinase that phosphorylates MyD88, promoted MyD88-dependent signaling and mediates dermatosis in Ptpn6spin mice. Our studies further demonstrated that SHP1 encoded by Ptpn6 binds and suppresses SYK activation to inhibit MyD88 phosphorylation. Downstream of SHP1 and SYK-dependent counterregulation of MyD88 tyrosine phosphorylation, we have demonstrated that the scaffolding function of receptor interacting protein kinase 1 (RIPK1) and tumor growth factor-β activated kinase 1 (TAK1)-mediating signaling were required to spur inflammatory disease. Overall, these studies identify SHP1 and SYK crosstalk as a critical regulator of MyD88 post-translational modifications and IL-1-driven inflammation.

Item Type: Paper
Uncontrolled Keywords: SHP1 Ptpn6 SYK IL-1α IL-1β MyD88 RIPK1 RIPK3 necrosis autoinflammation TAK1 myeloid cells MLKL
Subjects: diseases & disorders > inflammation
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > necrosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Tonks lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date: 18 April 2017
Date Deposited: 20 Apr 2017 21:07
Last Modified: 13 Jun 2018 15:59
Related URLs:
URI: http://repository.cshl.edu/id/eprint/34562

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