Control of Epidermal Growth Factor Receptor Endocytosis by Receptor Dimerization, Rather Than Receptor Kinase Activation

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2005 Aug 23

PMID 16113650

Citations 70

Authors

Qian Wang

Greg Villeneuve

Zhixiang Wang

Affiliations

Soon will be listed here.

Abstract

Given that ligand binding is essential for the rapid internalization of epidermal growth factor receptor (EGFR), the events induced by ligand binding probably contribute to the regulation of EGFR internalization. These events include receptor dimerization, activation of intrinsic tyrosine kinase activity and autophosphorylation. Whereas the initial results are controversial regarding the role of EGFR kinase activity in EGFR internalization, more recent data suggest that EGFR kinase activation is essential for EGFR internalization. However, we have shown here that inhibition of EGFR kinase activation by mutation or by chemical inhibitors did not block EGF-induced EGFR internalization. Instead, proper EGFR dimerization is necessary and sufficient to stimulate EGFR internalization. We conclude that EGFR internalization is controlled by EGFR dimerization, rather than EGFR kinase activation. Our results also define a new role for EGFR dimerization: by itself it can drive EGFR internalization, independent of its role in the activation of EGFR kinase.

Citing Articles

Cell Adhesion Molecules as Modulators of the Epidermal Growth Factor Receptor.

Kozlova I, Sytnyk V Cells. 2024; 13(22).

PMID: 39594667 PMC: 11592701. DOI: 10.3390/cells13221919.

Confinement energy landscape classification reveals membrane receptor nano-organization mechanisms.

Yu C, Richly M, Hoang T, El Beheiry M, Turkcan S, Masson J Biophys J. 2024; 123(13):1882-1895.

PMID: 38845200 PMC: 11267427. DOI: 10.1016/j.bpj.2024.06.001.

Photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes to promote PD-L1 multivalent binding for effective immune checkpoint blockade therapy.

Lee Y, Song S, Yang S, Kim J, Moon Y, Shim N Acta Pharm Sin B. 2024; 14(3):1428-1440.

PMID: 38487005 PMC: 10934337. DOI: 10.1016/j.apsb.2023.09.007.

Roles of epidermal growth factor receptor, claudin-1 and occludin in multi-step entry of hepatitis C virus into polarized hepatoma spheroids.

So C, Sourisseau M, Sarwar S, Evans M, Randall G PLoS Pathog. 2023; 19(12):e1011887.

PMID: 38157366 PMC: 10756512. DOI: 10.1371/journal.ppat.1011887.

Budding uninhibited by benzimidazoles-1 (BUB1) regulates EGFR signaling by reducing EGFR internalization.

Nyati S, Young G, Speers C, Nyati M, Rehemtulla A Aging (Albany NY). 2023; 15(13):6011-6030.

PMID: 37399454 PMC: 10373970. DOI: 10.18632/aging.204820.

References

Oved S, Yarden Y . Signal transduction: molecular ticket to enter cells. Nature. 2002; 416(6877):133-6. DOI: 10.1038/416133a. View

Bonifacino J, DellAngelica E . Molecular bases for the recognition of tyrosine-based sorting signals. J Cell Biol. 1999; 145(5):923-6. PMC: 2133128. DOI: 10.1083/jcb.145.5.923. View

Wang Y, Pennock S, Chen X, Wang Z . Endosomal signaling of epidermal growth factor receptor stimulates signal transduction pathways leading to cell survival. Mol Cell Biol. 2002; 22(20):7279-90. PMC: 139821. DOI: 10.1128/MCB.22.20.7279-7290.2002. View

Schlessinger J . Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell. 2002; 110(6):669-72. DOI: 10.1016/s0092-8674(02)00966-2. View

Garrett T, McKern N, Lou M, Elleman T, Adams T, Lovrecz G . Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha. Cell. 2002; 110(6):763-73. DOI: 10.1016/s0092-8674(02)00940-6. View

Jiang X, Huang F, Marusyk A, Sorkin A . Grb2 regulates internalization of EGF receptors through clathrin-coated pits. Mol Biol Cell. 2003; 14(3):858-70. PMC: 151565. DOI: 10.1091/mbc.e02-08-0532. View

Schmidt M, Furnari F, Cavenee W, Bogler O . Epidermal growth factor receptor signaling intensity determines intracellular protein interactions, ubiquitination, and internalization. Proc Natl Acad Sci U S A. 2003; 100(11):6505-10. PMC: 164476. DOI: 10.1073/pnas.1031790100. View

Duan L, Miura Y, Dimri M, Majumder B, Dodge I, Reddi A . Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis. J Biol Chem. 2003; 278(31):28950-60. DOI: 10.1074/jbc.M304474200. View

Chen W, LAZAR C, Poenie M, Tsien R, Gill G, Rosenfeld M . Requirement for intrinsic protein tyrosine kinase in the immediate and late actions of the EGF receptor. Nature. 1987; 328(6133):820-3. DOI: 10.1038/328820a0. View

10.

Honegger A, Szapary D, Schmidt A, Lyall R, Van Obberghen E, Dull T . A mutant epidermal growth factor receptor with defective protein tyrosine kinase is unable to stimulate proto-oncogene expression and DNA synthesis. Mol Cell Biol. 1987; 7(12):4568-71. PMC: 368145. DOI: 10.1128/mcb.7.12.4568-4571.1987. View

11.

Glenney Jr J, Chen W, LAZAR C, Walton G, Zokas L, Rosenfeld M . Ligand-induced endocytosis of the EGF receptor is blocked by mutational inactivation and by microinjection of anti-phosphotyrosine antibodies. Cell. 1988; 52(5):675-84. DOI: 10.1016/0092-8674(88)90405-9. View

12.

Felder S, Miller K, Moehren G, Ullrich A, Schlessinger J, Hopkins C . Kinase activity controls the sorting of the epidermal growth factor receptor within the multivesicular body. Cell. 1990; 61(4):623-34. DOI: 10.1016/0092-8674(90)90474-s. View

13.

Felder S, Lavin J, Ullrich A, Schlessinger J . Kinetics of binding, endocytosis, and recycling of EGF receptor mutants. J Cell Biol. 1992; 117(1):203-12. PMC: 2289403. DOI: 10.1083/jcb.117.1.203. View

14.

Spencer D, Wandless T, Schreiber S, Crabtree G . Controlling signal transduction with synthetic ligands. Science. 1993; 262(5136):1019-24. DOI: 10.1126/science.7694365. View

15.

Trowbridge I, Collawn J, Hopkins C . Signal-dependent membrane protein trafficking in the endocytic pathway. Annu Rev Cell Biol. 1993; 9:129-61. DOI: 10.1146/annurev.cb.09.110193.001021. View

16.

Heldin C . Dimerization of cell surface receptors in signal transduction. Cell. 1995; 80(2):213-23. DOI: 10.1016/0092-8674(95)90404-2. View

17.

Lamaze C, Schmid S . Recruitment of epidermal growth factor receptors into coated pits requires their activated tyrosine kinase. J Cell Biol. 1995; 129(1):47-54. PMC: 2120379. DOI: 10.1083/jcb.129.1.47. View

18.

Arteaga C, Ramsey T, Shawver L, Guyer C . Unliganded epidermal growth factor receptor dimerization induced by direct interaction of quinazolines with the ATP binding site. J Biol Chem. 1997; 272(37):23247-54. DOI: 10.1074/jbc.272.37.23247. View

19.

Wilde A, Beattie E, Lem L, Riethof D, Liu S, Mobley W . EGF receptor signaling stimulates SRC kinase phosphorylation of clathrin, influencing clathrin redistribution and EGF uptake. Cell. 1999; 96(5):677-87. DOI: 10.1016/s0092-8674(00)80578-4. View

20.

Sorkina T, Huang F, Beguinot L, Sorkin A . Effect of tyrosine kinase inhibitors on clathrin-coated pit recruitment and internalization of epidermal growth factor receptor. J Biol Chem. 2002; 277(30):27433-41. DOI: 10.1074/jbc.M201595200. View