Salivary phospholipid secretion in response to beta-adrenergic stimulation is mediated by Src kinase-dependent epidermal growth factor receptor transactivation.
Communication between receptor tyrosine kinase and G protein-coupled receptor (GPCR)-mediated signaling is recognized as a common integrator linking diverse aspects of intracellular signaling systems. Here, we report that G protein-coupled beta-adrenergic receptor activation leading to stimulation of salivary phospholipid release occurs with the involvement of epidermal growth factor receptor (EGFR). Using sublingual gland acinar cells, we show that prosecretory effect of isoproterenol on phospholipid release was subjected to suppression by EGFR kinase inhibitor, PD153035, and wortmannin, an inhibitor of PI3K, but not by PD98059, an inhibitor of extracellular signal regulated kinase (ERK). Furthermore, wortmannin, but not the ERK inhibitor, caused the reduction in the acinar cell secretory responses to beta-adrenergic agonist-generated cAMP as well as adenyl cyclase activator, forskolin. The acinar cell phospholipid secretory responses to isoproterenol, moreover, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR phosphorylation. Taken together, our data are the first to demonstrate the requirement for Src kinase-dependent EGFR transactivation in regulation of salivary phospholipid secretion in response to beta-adrenergic GPCR activation.
Slomiany
Bronislaw L
BL
Research Center, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103-2400, USA. slomiabr@umdnj.edu
Slomiany
Amalia
A
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000526:Alprenolol / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002794:Choline / Q000031:analogs & derivatives; D005576:Colforsin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D012463:Saliva / Q000201:enzymology / Q000378:metabolism*; D013361:Sublingual Gland / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015533:Transcriptional Activation; D000077191:Wortmannin; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C412373:AG 1879; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000730:Androstadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010743:Phospholipids; D011743:Pyrimidines; D011799:Quinazolines; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D003994:Bucladesine; D000526:Alprenolol; D066246:ErbB Receptors; D019061:src-Family Kinases; D007545:Isoproterenol; D002794:Choline; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline; D000077191:Wortmannin