Receptor-interacting protein kinase 4 and interferon regulatory factor 6 function as a signaling axis to regulate keratinocyte differentiation

Kwa, Mei Qi, Huynh, Jennifer, Aw, Jiamin, Zhang, Lianyi, Nguyen, Thao, Reynolds, Eric C., Sweet, Matthew J., Hamilton, John A. and Scholz, Glen M. (2014) Receptor-interacting protein kinase 4 and interferon regulatory factor 6 function as a signaling axis to regulate keratinocyte differentiation. Journal of Biological Chemistry, 289 45: 31077-31087. doi:10.1074/jbc.M114.589382

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Author Kwa, Mei Qi
Huynh, Jennifer
Aw, Jiamin
Zhang, Lianyi
Nguyen, Thao
Reynolds, Eric C.
Sweet, Matthew J.
Hamilton, John A.
Scholz, Glen M.
Title Receptor-interacting protein kinase 4 and interferon regulatory factor 6 function as a signaling axis to regulate keratinocyte differentiation
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 1083-351X
0021-9258
Publication date 2014-11-07
Year available 2014
Sub-type Article (original research)
DOI 10.1074/jbc.M114.589382
Open Access Status File (Publisher version)
Volume 289
Issue 45
Start page 31077
End page 31087
Total pages 11
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Subject 1303 Biochemistry
1312 Molecular Biology
1307 Cell Biology
Abstract Receptor-interacting protein kinase 4 (RIPK4) and interferon regulatory factor 6 (IRF6) are critical regulators of keratinocyte differentiation, and their mutation causes the related developmental epidermal disorders Bartsocas-Papas syndrome and popliteal pterygium syndrome, respectively. However, the signaling pathways in which RIPK4 and IRF6 operate to regulate keratinocyte differentiation are poorly defined. Here we identify and mechanistically define a direct functional relationship between RIPK4 and IRF6. Gene promoter reporter and in vitro kinase assays, coimmunoprecipitation experiments, and confocal microscopy demonstrated that RIPK4 directly regulates IRF6 trans-activator activity and nuclear translocation. Gene knockdown and overexpression studies indicated that the RIPK4-IRF6 signaling axis controls the expression of key transcriptional regulators of keratinocyte differentiation, including Grainyhead-like 3 and OVO-like 1. Additionally, we demonstrate that the p.Ile121Asn missense mutation in RIPK4, which has been identified recently in Bartsocas-Papas syndrome, inhibits its kinase activity, thereby preventing RIPK4-mediated IRF6 activation and nuclear translocation. We show, through mutagenesis-based experiments, that Ser-413 and Ser-424 in IRF6 are important for its activation by RIPK4. RIPK4 is also important for the regulation of IRF6 expression by the protein kinase C pathway. Therefore, our findings not only provide important mechanistic insights into the regulation of keratinocyte differentiation by RIPK4 and IRF6, but they also suggest one mechanism by which mutations in RIPK4 may cause epidermal disorders (e.g. Bartsocas-Papas syndrome), namely by the impaired activation of IRF6 by RIPK4.
Keyword Differentiation
Keratinocyte
Protein Kinase C (PKC)
Protein Phosphorylation
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 628769
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 28 Nov 2014, 01:29:25 EST by Anthony Yeates on behalf of Institute for Molecular Bioscience