Trans-autophosphorylation of ERBB2 heterodimers

Stable Identifier
Reaction [transition]
Homo sapiens
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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 the 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 an 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-oligomer 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
8617750 HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers

Fell, HP, Foy, L, Green, JM, Cohen, BD

J Biol Chem 1996
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, Rosenfeld, MG, Gill, GN, Chen, WS

J Biol Chem 1990
1706616 Identification of autophosphorylation sites of HER2/neu

Schlessinger, J, Zilberstein, A, Hazan, R, Ullrich, A, Dombalagian, M, Margolis, B

Cell Growth Differ 1990
2022652 Internalization and down-regulation of the human epidermal growth factor receptor are regulated by the carboxyl-terminal tyrosines

Beguinot, L, Helin, K

J Biol Chem 1991
16978839 Neuregulin-1 only induces trans-phosphorylation between ErbB receptor heterodimer partners

Mei, Y, Li, Z, Zhou, M, Liu, X

Cell Signal 2007
7478576 Analysis of protein-protein interactions involved in the activation of the Shc/Grb-2 pathway by the ErbB-2 kinase

Pertica, C, Belardo, G, Natali, PG, Chiari, R, Lanfrancone, L, Segatto, O, Pelicci, PG, Ricci, A

Oncogene 1995
18721752 System-wide investigation of ErbB4 reveals 19 sites of Tyr phosphorylation that are unusually selective in their recruitment properties

Lane, WS, MacBeath, G, Budnik, BA, Rush, J, Kaushansky, A, Gordus, A

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

Ratzkin, BJ, Klapper, L, Levkowitz, G, Seger, R, Alroy, I, Waterman, H, Sela, M, Yarden, Y, Lavi, S, Pinkas-Kramarski, R, Soussan, L

EMBO J 1996
12651161 Roles of mitogen-activated protein kinase and phosphoinositide 3'-kinase in ErbB2/ErbB3 coreceptor-mediated heregulin signaling

Vijapurkar, U, Koland, JG, Kim, MS

Exp Cell Res 2003
7556068 Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3

Issing, W, Niederfellner, G, Weiss, FU, Wallasch, C, Jallal, B, 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.

Howk, R, Margolis, BL, Kris, R, Schlessinger, J, Givol, D, Honegger, AM, Ullrich, A, Lax, I, Dombalagian, M

J Biol Chem 1989
Catalyst Activity

protein tyrosine kinase activity of ERBB2 heterodimers [plasma membrane]

This event is regulated