Reactome | Trans-autophosphorylation of ERBB2 heterodimers

Trans-autophosphorylation of ERBB2 heterodimers

Stable Identifier

R-HSA-1963582

Type

Reaction

Species

Homo sapiens

Compartment

extracellular region, cytosol, plasma membrane

Locations in the PathwayBrowser

Expand all

Summation

Dimers of ERBB2 and EGF-bound EGFR trans-autophosphorylate on six EGFR tyrosine residues and six ERBB2 tyrosine residues to form phosphorylated heterodimers that activate downstream signaling cascades (Ricci et al. 1995, Pinkas-Kramarski et al. 1996, Walton et al. 1990, Margolis et al. 1989, Hazan et al. 1990, Helin et al. 1991).

In heterodimers of ERBB2 and neuregulin-stimulated ERBB3, ERBB2 phosphorylates ERBB3 on tyrosine residues that serve as docking sites for p85 subunit of PI3K (Y1054, Y1197, Y1222, Y1224, Y1260, Y1276 and Y1289), as well as SHC1 (Y1328) and GRB7 (Y1199 and Y1262). Since ERBB3 lacks catalytic activity, it cannot phosphorylate ERBB2. Hovewer, since ERBB2:ERBB3 heterodimers usually oligomerize on the cell surface, ERBB2 can become trans-autophosphorylated by and adjacent ERBB2 protein. It is not known if ERBB2 in the ERBB2:ERBB3 hetero-oligomer is phosphorylated on all conserved tyrosine residues and if the phosphorylation status of ERBB2 in the ERBB2:ERBB3 hetero-oligoimer significantly affects signaling (Li et al. 2007, Pinkas-Kramarski et al. 1996, Prigent et al. 1994, Vijapurkar et al. 2003, Wallasch et al. 1995).

Heterodimers of ERBB2 and ERBB4 trans-autophosphorylate on tyrosine residues that serve as docking sites for PLC-gamma, GRB2 and SHC1, as well as p85 subunit of PI3K (PIK3R1) in the case of ERBB2 heterodimers with ERBB4 CYT1 isoforms (ERBB4cyt1) - ERBB4 JM-A CYT1 and ERBB4 JM-B-CYT1 (Li et al. 2007, Kaushansky et al. 2008, Hazan et al. 1990, Cohen et al. 1996).

Literature References

PubMed ID	Title	Journal	Year
1688559	Analysis of deletions of the carboxyl terminus of the epidermal growth factor receptor reveals self-phosphorylation at tyrosine 992 and enhanced in vivo tyrosine phosphorylation of cell substrates Walton, GM, Chen, WS, Rosenfeld, MG, Gill, GN	J Biol Chem	1990
8617750	HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers Cohen, BD, Green, JM, Foy, L, Fell, HP	J Biol Chem	1996
1706616	Identification of autophosphorylation sites of HER2/neu Hazan, R, Margolis, B, Dombalagian, M, Ullrich, A, Zilberstein, A, Schlessinger, J	Cell Growth Differ	1990
2022652	Internalization and down-regulation of the human epidermal growth factor receptor are regulated by the carboxyl-terminal tyrosines Helin, K, Beguinot, L	J Biol Chem	1991
16978839	Neuregulin-1 only induces trans-phosphorylation between ErbB receptor heterodimer partners Li, Z, Mei, Y, Liu, X, Zhou, M	Cell Signal	2007
7478576	Analysis of protein-protein interactions involved in the activation of the Shc/Grb-2 pathway by the ErbB-2 kinase Ricci, A, Lanfrancone, L, Chiari, R, Belardo, G, Pertica, C, Natali, PG, Pelicci, PG, Segatto, O	Oncogene	1995
18721752	System-wide investigation of ErbB4 reveals 19 sites of Tyr phosphorylation that are unusually selective in their recruitment properties Kaushansky, A, Gordus, A, Budnik, BA, Lane, WS, Rush, J, MacBeath, G	Chem Biol	2008
8026468	Identification of c-erbB-3 binding sites for phosphatidylinositol 3'-kinase and SHC using an EGF receptor/c-erbB-3 chimera Prigent, SA, Gullick, WJ	EMBO J	1994
8665853	Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions Pinkas-Kramarski, R, Soussan, L, Waterman, H, Levkowitz, G, Alroy, I, Klapper, L, Lavi, S, Seger, R, Ratzkin, BJ, Sela, M, Yarden, Y	EMBO J	1996
12651161	Roles of mitogen-activated protein kinase and phosphoinositide 3'-kinase in ErbB2/ErbB3 coreceptor-mediated heregulin signaling Vijapurkar, U, Kim, MS, Koland, JG	Exp Cell Res	2003
7556068	Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3 Wallasch, C, Weiss, FU, Niederfellner, G, Jallal, B, Issing, W, Ullrich, A	EMBO J	1995
2543678	All autophosphorylation sites of epidermal growth factor (EGF) receptor and HER2/neu are located in their carboxyl-terminal tails. Identification of a novel site in EGF receptor. Margolis, BL, Lax, I, Kris, R, Dombalagian, M, Honegger, AM, Howk, R, Givol, D, Ullrich, A, Schlessinger, J	J Biol Chem	1989