University of Oulu

Leena Rauhala, Tiina Jokela, Riikka Kärnä, Geneviève Bart, Piia Takabe, Sanna Oikari, Markku I. Tammi, Sanna Pasonen-Seppänen, Raija H. Tammi; Extracellular ATP activates hyaluronan synthase 2 (HAS2) in epidermal keratinocytes via P2Y2, Ca2+ signaling, and MAPK pathways. Biochem J 31 May 2018; 475 (10): 1755–1772. doi:

Extracellular ATP activates hyaluronan synthase 2 (HAS2) in epidermal keratinocytes via P2Y2, Ca2+ signaling, and MAPK pathways

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Author: Rauhala, Leena1; Jokela, Tiina1; Kärnä, Riikka1;
Organizations: 1Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland
2Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014 Oulun yliopisto, Finland
3Institute of Dentistry, University of Eastern Finland, FI-70211 Kuopio, Finland
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 8.5 MB)
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Language: English
Published: Portland Press, 2018
Publish Date: 2021-05-12


Extracellular nucleotides are used as signaling molecules by several cell types. In epidermis, their release is triggered by insults such as ultraviolet radiation, barrier disruption, and tissue wounding, and by specific nerve terminals firing. Increased synthesis of hyaluronan, a ubiquitous extracellular matrix glycosaminoglycan, also occurs in response to stress, leading to the attractive hypothesis that nucleotide signaling and hyaluronan synthesis could also be linked. In HaCaT keratinocytes, ATP caused a rapid and strong but transient activation of hyaluronan synthase 2 (HAS2) expression via protein kinase C-, Ca²⁺/calmodulin-dependent protein kinase II-, mitogen-activated protein kinase-, and calcium response element-binding protein-dependent pathways by activating the purinergic P2Y₂ receptor. Smaller but more persistent up-regulation of HAS3 and CD44, and delayed up-regulation of HAS1 were also observed. Accumulation of peri- and extracellular hyaluronan followed 4–6 h after stimulation, an effect further enhanced by the hyaluronan precursor glucosamine. AMP and adenosine, the degradation products of ATP, markedly inhibited HAS2 expression and, despite concomitant up-regulation of HAS1 and HAS3, inhibited hyaluronan synthesis. Functionally, ATP moderately increased cell migration, whereas AMP and adenosine had no effect. Our data highlight the strong influence of adenosinergic signaling on hyaluronan metabolism in human keratinocytes. Epidermal insults are associated with extracellular ATP release, as well as rapid up-regulation of HAS2/3, CD44, and hyaluronan synthesis, and we show here that the two phenomena are linked. Furthermore, as ATP is rapidly degraded, the opposite effects of its less phosphorylated derivatives facilitate a rapid shut-off of the hyaluronan response, providing a feedback mechanism to prevent excessive reactions when more persistent signals are absent.

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Series: Biochemical journal
ISSN: 0264-6021
ISSN-E: 1470-8728
ISSN-L: 0264-6021
Volume: 475
Issue: 10
Pages: 1755 - 1772
DOI: 10.1042/BCJ20180054
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
3111 Biomedicine
Funding: The present study was financially supported by grants from Sigrid Juselius Foundation (R.H.T., M.I.T., and S.P.-S.), the Special Government Funding of Kuopio University Hospital (M.I.T.), The Spearhead Funds of the University of Eastern Finland/Cancer Center of Eastern Finland (M.I.T. and R.H.T.), and The Cancer Foundation of Northern Savo (L.R.).
Copyright information: © Authors. Published by Portland Press Limited on behalf of the Biochemical Society. The final authenticated version is available online at