A negative-feedback loop regulating ERK1/2 activation and mediated by RasGPR2 phosphorylation.
The dynamic regulation of ERK1 and -2 (ERK1/2) is required for precise signal transduction controlling cell proliferation, differentiation, and survival. However, the underlying mechanisms regulating the activation of ERK1/2 are not completely understood. In this study, we show that phosphorylation of RasGRP2, a guanine nucleotide exchange factor (GEF), inhibits its ability to activate the small GTPase Rap1 that ultimately leads to decreased activation of ERK1/2 in cells. ERK2 phosphorylates RasGRP2 at Ser394 located in the linker region implicated in its autoinhibition. These studies identify RasGRP2 as a novel substrate of ERK1/2 and define a negative-feedback loop that regulates the BRaf-MEK-ERK signaling cascade. This negative-feedback loop determines the amplitude and duration of active ERK1/2.
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
Jinqi
J
Ren
Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
Aaron A
AA
Cook
Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
Wolfgang
W
Bergmeier
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.|Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.|Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
John
J
Sondek
D004789:Enzyme Activation; D025461:Feedback, Physiological / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D010766:Phosphorylation
D020662:Guanine Nucleotide Exchange Factors; C415483:RASGRP2 protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1
CalDAG-GEFI; ERK1/2 signaling; GEF; Negative-feedback loop; Phosphorylation; RasGRP2