Article

Differential activation of epidermal growth factor (EGF) receptor downstream signaling pathways by betacellulin and EGF

Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan. .
Endocrinology (Impact Factor: 4.64). 10/2004; 145(9):4232-43. DOI: 10.1210/en.2004-0401
Source: PubMed

ABSTRACT To determine the downstream signaling pathways regulated by betacellulin (BTC) in comparison with epidermal growth factor (EGF), we used Chinese hamster ovary cells overexpressing the human EGF receptor (ErbB1/EGFR). The overall time-dependent activation of EGFR autophosphorylation was identical in cells treated with 1 nm BTC or 1.5 nm EGF. Analysis of site-specific EGFR phosphorylation demonstrated that the BTC and EGF tyrosine phosphorylation of Y1086 was not significantly different. In contrast, the autophosphorylation of Y1173 was markedly reduced in BTC-stimulated cells, compared with EGF stimulation that directly correlated with a reduced BTC stimulation of Shc tyrosine phosphorylation, Ras, and Raf-1 activation. On the other hand, Y1068 phosphorylation was significantly increased after BTC stimulation, compared with EGF in parallel with a greater extent of Erk phosphorylation. Expression of a dominant interfering MEK kinase 1 (MEKK1) and Y1068F EGFR more efficiently blocked the enhanced Erk activation by BTC, compared with EGF. Interestingly BTC had a greater inhibitory effect on apoptosis, compared with EGF, and expression of Y1068F EGFR abolished this enhanced inhibitory effect. Together, these data indicated that although BTC and EGF share overlapping signaling properties, the ability of BTC to enhance Erk activation occurs independent of Ras. The increased BTC activation results from a greater extent of Y1068 EGFR tyrosine phosphorylation and subsequent increased recruitment of the Grb2-MEKK1 complex to the plasma membrane, compared with EGF stimulation. The increased Erk activation by BTC associated with antiapoptotic function.

0 Bookmarks
 · 
74 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The EGF receptor has seven different cognate ligands. Previous work has shown that these different ligands are capable of inducing different biological effects even in the same cell. To begin to understand the molecular basis for this variation, we used luciferase fragment complementation to measure ligand-induced dimer formation and radioligand binding to study the effect of the ligands on subunit-subunit interactions in EGFR homodimers and EGFR/ErbB2 heterodimers. In luciferase fragment complementation imaging studies, AREG functioned as a partial agonist, inducing only about half as much total dimerization as the other three ligands. However, unlike the other ligands, AREG showed biphasic kinetics for dimer formation suggesting that its path for EGF receptor activation involves binding to both monomers and preformed dimers. EGF, TGFα and BTC appear to mainly stimulate receptor activation through binding to and dimerization of receptor monomers. In radioligand binding assays, EGF and TGFα exhibited increased affinity for EGFR/ErbB2 heterodimers as compared to EGFR homodimers. By contrast, BTC and AREG showed a similar affinity for both dimers. Thus, EGF and TGFα are biased agonists while BTC and AREG are balanced agonists with respect to selectivity of dimer formation. These data suggest that the differences in biological response to different EGF receptor ligands may result from partial agonism for dimer formation, differences in the kinetic pathway utilized to generate activated receptor dimers and biases in the formation of heterodimers vs homodimers.
    Journal of Biological Chemistry 08/2014; 289(38). DOI:10.1074/jbc.M114.586826 · 4.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Type 1 diabetes is an autoimmune disease caused by permanent destruction of insulin-producing pancreatic β cells and requires lifelong exogenous insulin therapy. Recently, islet transplantation has been developed, and although there have been significant advances, this approach is not widely used clinically due to the poor survival rate of the engrafted islets. We hypothesized that improving survival of engrafted islets through ex vivo genetic engineering could be a novel strategy for successful islet transplantation. We transduced islets with adenoviruses expressing betacellulin, an epidermal growth factor receptor ligand, which promotes β-cell growth and differentiation, and transplanted these islets under the renal capsule of streptozotocin-induced diabetic mice. Transplantation with betacellulin-transduced islets resulted in prolonged normoglycemia and improved glucose tolerance compared with those of control virus-transduced islets. In addition, increased microvascular density was evident in the implanted islets, concomitant with increased endothelial von Willebrand factor immunoreactivity. Finally, cultured islets transduced with betacellulin displayed increased proliferation, reduced apoptosis and enhanced glucose-stimulated insulin secretion in the presence of cytokines. These experiments suggest that transplantation with betacellulin-transduced islets extends islet survival and preserves functional islet mass, leading to a therapeutic benefit in type 1 diabetes.
    Experimental and Molecular Medicine 05/2014; 46:e98. DOI:10.1038/emm.2014.24 · 2.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chemotherapy is one of the important methods for treatment in tumors. However, many tumor patients may experience tumor recurrence because of treatment failure due to chemoresistance. Although many signaling pathways could influence chemoresistance of tumor cells, the extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway has gained significant attention because of its implications in signaling and which has crosstalk with other signaling pathways. Extensive studies conclude that ERK1/2 pathway is responding to chemoresistance in many kinds of malignant tumors. The aim of this review is to discuss on the role of ERK1/2 pathway in chemoresistance and therapy of tumors. A comprehensive understanding of ERK1/2 pathway in chemoresistance of tumors could provide novel avenues for treatment strategies of tumors. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Bioorganic & Medicinal Chemistry Letters 12/2014; 25(2). DOI:10.1016/j.bmcl.2014.11.076 · 2.33 Impact Factor

Preview

Download
0 Downloads