P2Y2 nucleotide receptor up-regulation and function in submandibular gland epithelium

"May 2005"The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Vita.Dissertations, Academic -- University of Missouri--Columbia -- pharmacology.Thesis (Ph. D.) University of Missouri-Columbia 2005.Includes bibliographical references.Sjögren's syndrome (SS) is an autoimmune disease that specifically targets exocrine glands, including salivary glands, and results in an impairment of secretory function. P2Y₂ nucleotide receptors for extracellular ATP and UTP are up-regulated in response to stress or injury in a variety of tissues including submandibular glands (SMGs). Therefore, our objective was to assess whether P2Y₂ receptor expression is up-regulated in SMGs of the NOD.B10 mouse model of SS, and to determine the function of P2Y₂Rs in salivary gland tissue. Our data indicate that P2Y₂Rs are up-regulated in SMGs of the NOD.B10 mice, and this up-regulation increases as the disease progresses. Moreover, data obtained using a human submandibular gland cell line, demonstrate that P2Y₂Rs activate a signaling pathway leading to gene transcription via at least two distinct mechanisms. These findings suggest that regulation of P2Y₂Rs is likely to be an important therapeutic target for various diseases

Prospectus, February 28, 1996

https://spark.parkland.edu/prospectus_1996/1006/thumbnail.jp

Phosphorylation of EGFR, ERK 1/2 and downstream transcription factors after P2Y2 receptor activation in a human submandibular gland cell line

Abstract only availableP2 nucleotide receptors mediate a variety of biological responses and are activated by the extracellular nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), uridine triphosphate (UTP), uridine diphosphate (UDP). The P2Y2 nucleotide receptor is a seven transmembrane spanning domain receptor activated by the nucleotides ATP and UTP, and is up-regulated in a variety of tissues in response to injury or stress. For example, the P2Y2 receptors are not normally expressed in salivary glands, but upon disruption of tissue homeostasis, the P2Y2 receptors are up-regulated. Sjogren's disease is an autoimmune disorder that affects salivary and lacrimal glands resulting in a decreased ability to produce saliva and tears. Previous work by our lab has shown that the P2Y2 receptor is up-regulated in submandibular glands of a Sjogren's syndrome mouse model, suggesting that it may be up-regulated in human Sjogren's syndrome. The goal of this project is to analyze the function of P2Y2 receptors in salivary gland tissues. HSG cells, which endogenously express P2Y2 receptors and are derived from a human submandibular gland tumor, were utilized as a cell model to analyze downstream signaling pathways in response to UTP. Our results show that UTP, the P2Y2 receptor selective agonist, causes phosphorylation of the epidermal growth factor receptor (EGFR), extracellular regulated kinases (ERK 1/2) and the downstream transcription factors p90RSK, and ELK, suggesting that P2Y2 receptors may play a role in gene transcription in salivary gland tissues.NSF-REU Biology & Biochemistr

Prospectus, April 24, 1996

https://spark.parkland.edu/prospectus_1996/1013/thumbnail.jp

Prospectus, December 6, 1995

https://spark.parkland.edu/prospectus_1995/1032/thumbnail.jp

Prospectus, March 27, 1996

https://spark.parkland.edu/prospectus_1996/1009/thumbnail.jp

Prospectus, April 17, 1996

https://spark.parkland.edu/prospectus_1996/1012/thumbnail.jp

Prospectus, May 8, 1996

https://spark.parkland.edu/prospectus_1996/1015/thumbnail.jp

P2Y2 receptors Transactivate the EGFR/ERB1 and ERB3 Growth Factor Receptors in Human Salivary Gland Cells [abstract]

Abstract only availableThe epidermal growth factor receptor (EGFR/ERB1) plays a key role in the regulation of epithelial cell development, differentiation and in the pathophysiology of hyperproliferative diseases such as cancer. Transactivation of the EGFR/ERB1 by G-protein coupled receptors has been shown to be dependent on proteolytic cleavage of membrane ligands such as heparin binding epidermal growth factor (HBEGF), EGF, transforming growth factor (TGF-), epiregulin, amphiregulin and betacellulin. Utilizing the human submandibular gland (HSG) cell line, we found that activation of the P2Y2 nucleotide receptor (P2Y2R) by its agonist UTP caused a time-dependent activation of EGFR/ERB1; however, neutralizing antibodies to the known ligands to EGFR/ERB1 failed to inhibit the UTP-induced phosphorylation of EGFR/ERB1. EGFR/ERB1 phosphorylation can also be induced by heterodimerization with one of the other ERB family members, ERB2, ERB3, and ERB4. HSG cells express ERB2 and ERB3 but not ERB4. Since ERB2 is a ligandless receptor, ERB3 is the likely dimerizing partner. Our results indicate that P2Y2R activation by UTP phosphorylates ERB3. Heregulin, the only known ligand for ERB3 is expressed in HSGs. Therefore, our results suggest that P2Y2R activation stimulates the formation of ERB3-EGFR/ERB1 heterodimers by cleavage of heregulin and its binding to ERB3