Threonine 454 phosphorylation in Grainyhead-like 3 is important for its function and regulation by the p38 MAPK pathway
| Autor: | Grzegorz Kotarba, Tomasz Wilanowski, Agnieszka Kikulska, Ewa Krzywinska, Marek Dominick Zorawski, Katarzyna Kwiatkowska, Michal Mlacki, Agnieszka Taracha |
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| Rok vydání: | 2018 |
| Předmět: |
Keratinocytes
Threonine 0301 basic medicine Skin Neoplasms p38 mitogen-activated protein kinases Polymorphism Single Nucleotide p38 Mitogen-Activated Protein Kinases Cell Line 03 medical and health sciences chemistry.chemical_compound Downregulation and upregulation Animals Humans Point Mutation Amino Acid Sequence Phosphorylation Molecular Biology Gene Transcription factor Methionine integumentary system Cell Biology Cell biology Cleft Palate DNA-Binding Proteins 030104 developmental biology chemistry Cell culture Signal Transduction Transcription Factors |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1865:1002-1011 |
| ISSN: | 0167-4889 |
| DOI: | 10.1016/j.bbamcr.2018.04.010 |
| Popis: | The mammalian Grainyhead-like 3 (GRHL3) transcription factor is essential for epithelial development and plays a protective role against squamous cell carcinoma of the skin and of the oral cavity. A single nucleotide polymorphism (SNP) in GRHL3, rs141193530 (p.P455A), is associated with non-melanoma skin cancer in human patients. Moreover, it is known that this SNP, as well as another variant, rs41268753 (p.T454M), are associated with nonsyndromic cleft palate and that rs41268753 negatively affects GRHL3 transcriptional activity. These SNPs are located in adjacent codons of the GRHL3 gene, and the occurrence of either SNP abolishes a putative threonine-proline phosphorylation motif at T454 in the encoded protein. The role of phosphorylation in regulating mammalian GRHL function is currently unknown. In this work we show that GRHL3 is phosphorylated at several residues in a human keratinocyte cell line, among them at T454. This site is essential for the full transcriptional activity of GRHL3. The T454 residue is phosphorylated by p38 MAPK in vitro and activation of p38 signaling in cells causes an increase in GRHL3 activity. The regulation of GRHL3 function by this pathway is dependent on T454, as the substitution of T454 with methionine inhibits the activation of GRHL3. Taken together, our results show that T454 is one of the phosphorylated residues in GRHL3 in keratinocytes and this residue is important for the upregulation of GRHL3 transcriptional activity by the p38 pathway. |
| Databáze: | OpenAIRE |
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