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.
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.
From the Institutes of Biomedicine and tiina.jokela@gmail.com.
Tiina A
TA
Jokela
From the Institutes of Biomedicine and.
Riikka
R
Kärnä
From the Institutes of Biomedicine and Dentistry, School of Medicine, University of Eastern Finland, P. O. Box 1627, FIN-70210 Kuopio, Finland.
Katri M
KM
Makkonen
From the Institutes of Biomedicine and.
Jarmo T
JT
Laitinen
From the Institutes of Biomedicine and.
Raija H
RH
Tammi
From the Institutes of Biomedicine and.
Markku I
MI
Tammi
D020816:Amino Acid Motifs; D002465:Cell Movement; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014532:Uridine Diphosphate Glucose / Q000378:metabolism*
C518528:P2Y14 receptor, human; D018048:Receptors, Purinergic P2; D050796:STAT3 Transcription Factor; D014443:Tyrosine; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D014532:Uridine Diphosphate Glucose
Hyaluronan; Hyaluronate; Janus Kinase (JAK); Keratinocyte; P2Y14; Purinergic Receptor; STAT3; UDP-Glc