Reactome | EGFR autophosphorylation

EGFR autophosphorylation

Stable Identifier

R-HSA-177934

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol, plasma membrane, extracellular region

ReviewStatus

5/5

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The cytoplasmic domain of EGFR contains tyrosine, serine and threonine phosphorylation sites. Dimerization of EGFR activates its intrinsic protein kinase activity and results in autophosphorylation of 6 tyrosine residues in the cytoplasmic tail of EGFR. Tyrosine autophosphorylation is crucial for normal receptor signaling. Five of these tyrosine residues (Y1016 i.e. Y992 in the mature protein, Y1092 i.e. Y1068 in the mature protein, Y1110 i.e. Y1086 in the mature protein, Y1172 i.e. Y1148 in the mature protein and Y1197 i.e. Y1173 in the mature protein ) serve as specific binding sites for cytosolic target proteins involved in signal transmission, while the tyrosine residue Y1069 i.e. Y1045 in the mature protein is involved in recruitment of CBL ubiquitin ligase and downregulation of EGFR signaling through degradation of activated EGFR.

Binding of EGFR to FAM83B positively regulates both basal and EGF-induced trans-autophosphorylation of EGFR through an unknown mechanism. FAM83B is released from autophosphorylated EGFR (Cipriano et al. 2014). FAM83B positively regulates activation of AKT and MAPK signaling downstream of EGFR (Cipriano et al. 2012), consistent with its positive effect on EGFR trans-autophosphorylation. FAM83A positively regulates EGFR signaling, and may act as an EGFR effector as it is tyrosine phosphorylated upon EGFR activation and able to activate RAF and PI3K signaling (Lee et al. 2012). Direct binding of FAM83A to EGFR has not been reported, but the lysine residue K230 that is necessary for interaction of FAM83B with EGFR is conserved in FAM83A (Cipriano et al. 2014). FAM83A-AS1 lncRNA, known to increase FAM83A expression, positively regulates EGFR protein level (Zhao et al. 2022).

FAM83D, highly expressed in invasive epithelial ovarian cancer, positively regulates activating tyrosine phosphorylation of EGFR, as well as activating phosphorylation of EGFR downstream effectors CRAF, ERK1/2 (MAPK3/1), and AKT (Zhang et al. 2019). Direct binding of FAM83D to EGFR has not been reported, but the lysine residue K230 that is necessary for interaction of FAM83B with EGFR is conserved in FAM83D (Cipriano et al. 2014).

FAM83A and FAM83D are annotated as candidate binding partners or EGFR and as candidate positive regulators of EGFR trans-autophosphorylation.

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
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
23912460	Hyperactivation of EGFR and downstream effector phospholipase D1 by oncogenic FAM83B Cipriano, R, Bryson, BL, Miskimen, KL, Bartel, CA, Hernandez-Sanchez, W, Bruntz, RC, Scott, SA, Lindsley, CW, Brown, HA, Jackson, MW	Oncogene	2014
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