The molecular mechanism of EGF receptor activation in pancreatic β-cells by thyrotropin-releasing hormone

Abstract

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.

Secreted phospholipase A2-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding

“…Therefore, our results suggest that Src contributes to sPLA 2 -IIA-induced EGFR transactivation at various steps: Src may serve as an upstream component of EGFR transactivation by phosphorylating Tyr 845 directly and indirectly by a MMPs/ADAMs/HB-EGF-dependent mechanism. These findings are consistent with abundant evidence indicating that external stimuli can transactivate EGFR in complex Src-dependent signaling [62-64]. Further studies are required to clarify the precise role of Src in this system, as well as to determine which member(s) of the family (Src, Fyn, and Yes) is involved in sPLA 2 -IIA-induced EGFR transactivation and BV-2 cells activation.…”

Bone marrow increases human islets insulin positive cells in co-culture: quantification with flow cytometry

“…Insulin concentrations were measured and calculated using a μQuant microplate reader equipped with KC Junior ® microplate reader software (Bio-Tek Instruments, Inc., Winooski, VT) [24]. Briefly, insulin standards and appropriately diluted samples were added to 96-well microplates precoated by the manufacturer with an anti-insulin antibody and incubated for 1 hour at room temperature.…”

Receptor transactivation cascades. Focus on “Effects of α1D-adrenergic receptors on shedding of biologically active EGF in freshly isolated lacrimal gland epithelial cells”

“…Overexpression, as well as transactivation, of EGFRs plays a prominent role in regulating tumor growth and survival. EGFR transactivation has been shown to play a potential role in cancers, such as the prostate (20,27), ovarian (22), colon (23), and breast (3). Transactivation of the EGFR results in intracellular signaling that leads to growth, proliferation, and migration of cancer cells (4,6).…”