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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Cell Movement
  • Glucuronosyltransferase / genetics*
  • Glucuronosyltransferase / metabolism
  • Humans
  • Hyaluronan Synthases
  • Hyaluronic Acid / biosynthesis*
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Keratinocytes / enzymology
  • Keratinocytes / metabolism*
  • Phosphorylation
  • Promoter Regions, Genetic*
  • Protein Binding
  • Receptors, Purinergic P2 / genetics
  • Receptors, Purinergic P2 / metabolism*
  • STAT3 Transcription Factor / chemistry
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Tyrosine / chemistry
  • Tyrosine / genetics
  • Tyrosine / metabolism*
  • Up-Regulation
  • Uridine Diphosphate Glucose / metabolism*


  • P2Y14 receptor, human
  • Receptors, Purinergic P2
  • STAT3 Transcription Factor
  • Tyrosine
  • Hyaluronic Acid
  • Glucuronosyltransferase
  • HAS2 protein, human
  • Hyaluronan Synthases
  • JAK2 protein, human
  • Janus Kinase 2
  • Uridine Diphosphate Glucose