Rapgef2 Connects GPCR-Mediated cAMP Signals to ERK Activation in Neuronal and Endocrine Cells

被引:50
作者
Emery, Andrew C. [1 ]
Eiden, Maribeth V. [2 ]
Mustafa, Tomris [1 ]
Eiden, Lee E. [1 ]
机构
[1] NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Intramural Res Program, Bethesda, MD 20892 USA
[2] NIMH, Sect Directed Gene Transfer, Lab Cellular & Mol Regulat, Intramural Res Program, Bethesda, MD 20892 USA
关键词
NUCLEOTIDE-EXCHANGE FACTOR; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; NERVE GROWTH-FACTOR; DROSOPHILA PDZ-GEF; PROTEIN-KINASE; FACTOR CNRASGEF; CYCLIC-AMP; SYNAPTIC PLASTICITY; POLYPEPTIDE PACAP; PC12; CELLS;
D O I
10.1126/scisignal.2003993
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
G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR)-mediated increases in the second messenger cyclic adenosine monophosphate (cAMP) activate the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK), and in neuroendocrine cells, this pathway leads to cAMP-dependent neuritogenesis mediated through Rap1 and B-Raf. We found that the Rap guanine nucleotide exchange factor Rapgef2 was enriched from primary bovine neuroendocrine cells by cAMP-agarose affinity chromatography and that it was specifically eluted by cAMP. With loss-of-function experiments in the rat neuronal cell line Neuroscreen-1 (NS-1) and gain-of-function experiments in human embryonic kidney 293T cells, we demonstrated that Rapgef2 connected GPCR-dependent activation of adenylate cyclase and increased cAMP concentration with the activation of ERK in neurons and endocrine cells. Furthermore, knockdown of Rapgef2 blocked cAMP-and ERK-dependent neuritogenesis. Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity.
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页数:12
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