NGF- and MAPK-dependent EGR1, EGR2 and EGR4 expression

Stable Identifier
Reaction [omitted]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

The Early Growth Response (EGR) gene family includes EGR1-4 and WT1. These Cys2-His2 zinc finger transcription factors are immediate early genes (IEG) that are rapidly turned on downstream of a number of stimuli and regulate expression of genes involved in stress response and differentiation (reviewed in Pagel and Deindl, 2001; Bahrami and Drabløs, 2016). Roles for EGR proteins are well established in the nervous system, with EGR target genes contributing to synaptic plasticity, long-term potentiation, peripheral nerve myelination and NGF-induced neurite outgrowth (reviewed in Perez-Cadahia et al, 2011; Herdegen and Leah, 1998; O'Donovan et al, 1999).
Expression of EGR genes depends on binding of phosphorylated ternary complex factor (TCF) protein ELK1 and its transcriptional coactivator SRF (serum response factor) to their cognate DNA binding sequences in the promoters (Hooker et al, 2017; De Franco et al, 1993; Harada et al, 2001; reviewed in Herdegen and Leah, 1998). NGF-stimulated expression of EGR1 and 2 occurs downstream of sustained MAPK signaling (Millbrandt et al, 1987; Sukhatme et al, 1988; de Franco et al, 1998; Mullenbrock et al, 2011; Crosby et al, 1991; Lönn et al, 2005). In addition to SRF and TCF binding sites, the EGR1 promoter also contain consensus binding sequences for AP-1 and CREB, as well as binding sites for EGR1 protein itself (Schwachtgen et al, 2000; Thiel et al, 2000; Svaren et al, 1996; reviewed in Page; and Deindl, 2001). Expression of EGR1 is limited by a negative feedback loop mediated by the binding of a complex of EGR1 with a repressor protein of the NAB family (NGF1A binding protein) to the EGR1 binding site (Cao et al, 1990; Thiel et al, 2000; Svaren et al, 1996).

Literature References
PubMed ID Title Journal Year
2072895 The early response gene NGFI-C encodes a zinc finger transcriptional activator and is a member of the GCGGGGGCG (GSG) element-binding protein family

Simburger, KS, Puetz, JJ, Milbrandt, J, Fahrner, TJ, Crosby, SD

Mol. Cell. Biol. 1991
11018254 The human transcriptional repressor protein NAB1: expression and biological activity

Magin, A, Kaufmann, K, Thiel, G, Cramer, M, Bach, K, Lietz, M

Biochim. Biophys. Acta 2000
22053691 Early growth response 1--a transcription factor in the crossfire of signal transduction cascades

Deindl, E, Pagel, JI

Indian J. Biochem. Biophys. 2011
11331872 ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1

Harada, T, Nishida, E, Ogawa, S, Morooka, T

Nat. Cell Biol. 2001
22065583 Global expression analysis identified a preferentially nerve growth factor-induced transcriptional program regulated by sustained mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) and AP-1 protein activation during PC12 cell differentiation

Cooper, GM, Mullenbrock, S, Shah, J

J. Biol. Chem. 2011
8483478 Nerve growth factor induces transcription of NGFIA through complex regulatory elements that are also sensitive to serum and phorbol 12-myristate 13-acetate

Endoh, M, DeFranco, C, Wagner, JA, Damon, DH

Mol. Endocrinol. 1993
3672127 A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor

Milbrandt, J

Science 1987
3127059 A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization

Le Beau, MM, Stamenkovich, D, Cao, XM, Cohen, DR, Chang, LC, Adamson, ED, Sukhatme, VP, Curran, T, Shows, TB, Tsai-Morris, CH, Edwards, SA, Ferreira, PC

Cell 1988
10203854 The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience

Baraban, JM, Millbrandt, J, Tourtellotte, WG, O'Donovan, KJ

Trends Neurosci. 1999
2109185 Identification and characterization of the Egr-1 gene product, a DNA-binding zinc finger protein induced by differentiation and growth signals

Koski, RA, Gashler, A, Cao, XM, Sukhatme, VP, McKiernan, M, Hay, RV, Gaffney, R, Morris, CF

Mol. Cell. Biol. 1990
9858769 Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins

Leah, JD, Herdegen, T

Brain Res. Brain Res. Rev. 1998
28275114 Binding and inhibition of the ternary complex factor Elk-4/Sap1 by the adapter protein Dok-4

Roodman, V, Lemay, S, Takano, T, Hooker, E, Baldwin, C, Isa, NN, Batra, A

Biochem. J. 2017
16187211 BMP enhances transcriptional responses to NGF during PC12 cell differentiation

Kylberg, A, Zaia, K, Lönn, P, Israelsson, C, Usoskin, D, Ebendal, T, Althini, S

Neurochem. Res. 2005
7624335 Identification of NAB1, a repressor of NGFI-A- and Krox20-mediated transcription

Russo, MW, Milbrandt, J, Sevetson, BR

Proc. Natl. Acad. Sci. U.S.A. 1995
10826704 Full promoter sequence of human early growth response factor-1 (Egr-1): demonstration of a fifth functional serum response element

Braddock, M, Campbell, CJ, Schwachtgen, JL

DNA Seq. 2000
21326363 Activation and function of immediate-early genes in the nervous system

Pérez-Cadahía, B, Davie, JR, Drobic, B

Biochem. Cell Biol. 2011
27220739 Gene regulation in the immediate-early response process

Drabløs, F, Bahrami, S

Adv Biol Regul 2016
This event is regulated