The molecular mechanism of EGF receptor activation in pancreatic beta-cells by thyrotropin-releasing hormone.
Thyrotropin-releasing hormone (TRH) and its receptor subtype TRH receptor-1 (TRHR1) are found in pancreatic beta-cells, and it has been shown that TRH might have potential for autocrine/paracrine regulation through the TRHR1 receptor. In this paper, TRHR1 is studied to find whether it can initiate multiple signal transduction pathways to activate the epidermal growth factor (EGF) receptor in pancreatic beta-cells. By initiating TRHR1 G protein-coupled receptor (GPCR) and dissociated alphabetagamma-complex, TRH (200 nM) activates tyrosine residues at Tyr845 (a known target for Src) and Tyr1068 in the EGF receptor complex of an immortalized mouse beta-cell line, betaTC-6. Through manipulating the activation of Src, PKC, and heparin-binding EGF-like growth factor (HB-EGF), with corresponding individual inhibitors and activators, multiple signal transduction pathways linking TRH to EGF receptors in betaTC-6 cell line have been revealed. The pathways include the activation of Src kinase and the release of HB-EGF as a consequence of matrix metalloproteinase (MMP)-3 activation. Alternatively, TRH inhibited PKC activity by reducing the EGF receptor serine/threonine phosphorylation, thereby enhancing tyrosine phosphorylation. TRH receptor activation of Src may have a central role in mediating the effects of TRH on the EGF receptor. The activation of the EGF receptor by TRH in multiple circumstances may have important implications for pancreatic beta-cell biology.
Luo
LuGuang
L
The Center for Stem Cell Biology, Department of Research, Roger Williams Hospital, 825 Chalkstone Ave., Providence, RI 02908, USA.
Yano
Naohiro
N
Luo
John Z Q
JZ
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D066257:Heparin-binding EGF-like Growth Factor; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
C412373:AG 1879; D000906:Antibodies; D004791:Enzyme Inhibitors; D044387:GTP-Binding Protein beta Subunits; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011743:Pyrimidines; D018025:Receptors, Thyrotropin-Releasing Hormone; D014443:Tyrosine; D013973:Thyrotropin-Releasing Hormone; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019061:src-Family Kinases; D011493:Protein Kinase C