Glucagon promotes cAMP-response element-binding protein phosphorylation via activation of ERK1/2 in MIN6 cell line and isolated islets of Langerhans

被引:59
作者
Dalle, S
Longuet, C
Costes, S
Broca, C
Faruque, O
Fontés, G
Hani, EH
Bataille, D
机构
[1] CHU Arnaud de Villeneuve, INSERM, U376, F-34295 Montpellier 5, France
[2] Fac Med Montpellier, Inst Biol, CNRS, UMR 5160, F-34060 Montpellier 1, France
关键词
D O I
10.1074/jbc.M312483200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
By using the MIN6 cell line and pancreatic islets, we show that in the presence of a low glucose concentration, corresponding to physiological glucagon release from alpha cells, glucagon treatment of the beta cell caused a rapid, time-dependent phosphorylation and activation of p44/p42 mitogen-activated protein kinase (ERK1/2) independently from extracellular calcium influx. Inhibition of either cAMP-dependent protein kinase (PKA) or MEK completely blocked ERK1/2 activation by glucagon. However, no significant activation of several upstream activators of MEK, including Shc-p21(Ras) and phosphatidylinositol 3-kinase, was observed in response to glucagon treatment. Chelation of intracellular calcium (intracellular [Ca2+]) reduced glucagon-mediated ERK1/2 activation. In addition, internalization of glucagon receptors through clathrin-coated pits formation is required for ERK1/2 activation. Remarkably, glucagon promotes the nuclear translocation of ERK1/2 and induces the phosphorylation of cAMP-response element-binding protein (CREB). Miniglucagon, produced from glucagon and released together with the mother hormone from the alpha cells in low glucose situations, blocks the insulinotropic effect of glucagon, whereas it does not inhibit the glucagon-induced PKA/ERK1/2/CREB pathway. We conclude that glucagon-induced ERK1/2 activation is mediated by PKA and that an increase in [Ca2+](i) is required for maximal ERK activation. Our results uncover a novel mechanism by which the PKA/ERK1/2 signaling network engaged by glucagon, in situation of low glucose concentration, regulates phosphorylation of CREB, a transcription factor crucial for normal beta cell function and survival.
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页码:20345 / 20355
页数:11
相关论文
共 44 条
[1]   Regulation of ERK1 and ERK2 by glucose and peptide hormones in pancreatic β cells [J].
Arnette, D ;
Gibson, TB ;
Lawrence, MC ;
January, B ;
Khoo, S ;
McGlynn, K ;
Vanderbilt, CA ;
Cobb, MH .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (35) :32517-32525
[2]   Rapid activation and nuclear translocation of mitogen-activated protein kinases in response to physiological concentration of glucose in the MIN6 pancreatic β cell line [J].
Benes, C ;
Roisin, MP ;
Van Tan, H ;
Creuzet, C ;
Miyazaki, J ;
Fagard, R .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (25) :15507-15513
[3]  
BIRNBAUMER L, 1995, J RECEPT SIGNAL TR R, V15, P213
[4]   Ras mediates the cAMP-dependent activation of extracellular signal-regulated kinases (ERKs) in melanocytes [J].
Buscà, R ;
Abbe, P ;
Mantoux, F ;
Aberdam, E ;
Peyssonnaux, C ;
Eychène, A ;
Ortonne, JP ;
Ballotti, R .
EMBO JOURNAL, 2000, 19 (12) :2900-2910
[5]   Mammalian MAP kinase signalling cascades [J].
Chang, LF ;
Karin, M .
NATURE, 2001, 410 (6824) :37-40
[6]   NUCLEAR-LOCALIZATION AND REGULATION OF ERK-ENCODED AND RSK-ENCODED PROTEIN-KINASES [J].
CHEN, RH ;
SARNECKI, C ;
BLENIS, J .
MOLECULAR AND CELLULAR BIOLOGY, 1992, 12 (03) :915-927
[7]   Insulin-like growth factor-1 receptor internalization regulates signaling via the Shc/mitogen-activated protein kinase pathway, but not the insulin receptor substrate-1 pathway [J].
Chow, JC ;
Condorelli, G ;
Smith, RJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (08) :4672-4680
[8]   Role of growth hormone in glucose counterregulation [J].
Cryer, PE .
HORMONE RESEARCH, 1996, 46 (4-5) :192-194
[9]   Two cytoplasmic loops of the glucagon receptor are required to elevate cAMP or intracellular calcium [J].
Cypess, AM ;
Unson, CG ;
Wu, CR ;
Sakmar, TP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (27) :19455-19464
[10]   Switching of the coupling of the beta(2)-adrenergic receptor to different G proteins by protein kinase A [J].
Daaka, Y ;
Luttrell, LM ;
Lefkowitz, RJ .
NATURE, 1997, 390 (6655) :88-91