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J Biol Chem. 2014 Jun 27;289(26):18569-81. doi: 10.1074/jbc.M114.551804. Epub 2014 May 20.

Extracellular UDP-glucose activates P2Y14 Receptor and Induces Signal Transducer and Activator of Transcription 3 (STAT3) Tyr705 phosphorylation and binding to hyaluronan synthase 2 (HAS2) promoter, stimulating hyaluronan synthesis of keratinocytes.

Author information

1
From the Institutes of Biomedicine and tiina.jokela@gmail.com.
2
From the Institutes of Biomedicine and.
3
From the Institutes of Biomedicine and Dentistry, School of Medicine, University of Eastern Finland, P. O. Box 1627, FIN-70210 Kuopio, Finland.

Abstract

Hyaluronan, a major matrix molecule in epidermis, is often increased by stimuli that enhance keratinocyte proliferation and migration. We found that small amounts of UDP-sugars were released from keratinocytes and that UDP-glucose (UDP-Glc) added into keratinocyte cultures induced a specific, rapid induction of hyaluronan synthase 2 (HAS2), and an increase of hyaluronan synthesis. The up-regulation of HAS2 was associated with JAK2 and ERK1/2 activation, and specific Tyr(705) phosphorylation of transcription factor STAT3. Inhibition of JAK2, STAT3, or Gi-coupled receptors blocked the induction of HAS2 expression by UDP-Glc, the latter inhibitor suggesting that the signaling was triggered by the UDP-sugar receptor P2Y14. Chromatin immunoprecipitations demonstrated increased promoter binding of Tyr(P)(705)-STAT3 at the time of HAS2 induction. Interestingly, at the same time Ser(P)(727)-STAT3 binding to its response element regions in the HAS2 promoter was unchanged or decreased. UDP-Glc also stimulated keratinocyte migration, proliferation, and IL-8 expression, supporting a notion that UDP-Glc signals for epidermal inflammation, enhanced hyaluronan synthesis as an integral part of it.

KEYWORDS:

Hyaluronan; Hyaluronate; Janus Kinase (JAK); Keratinocyte; P2Y14; Purinergic Receptor; STAT3; UDP-Glc

PMID:
24847057
PMCID:
PMC4140273
DOI:
10.1074/jbc.M114.551804
[Indexed for MEDLINE]
Free PMC Article

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