[Frontiers in Bioscience 8, s28-38, January 1, 2003]

FUNCTIONAL IMPLICATION OF THE INTERACTION BETWEEN EGF RECEPTOR AND C-SRC

Tzeng-Horng Leu 1 and Ming-Chei Maa 2

1 Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan 70101, R.O.C.

2 Institute of Biochemistry, Chung Shan Medical University, Taichung, Taiwan, R.O.C.

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. The EGFR family tyrosine kinases
3.1. The EGFR structure and autophosphorylation
3.2. Identification of EGFR substrates
3.3. Downregulation of EGFR
4. The Src family tyrosine kinases
4.1. The Src structure and regulation of Src activity
4.1.1. Regulation of Src activity by mutation
4.1.2. Regulation of Src activity by modification other than pTyr-416 and -527
4.1.3. Regulation of Src activity by interacting with proteins
4.2. The targets of c-Src
4.2.1. Focal adhesion kinase
4.2.2. Clathrin
4.2.3. Cortactin
4.2.4. Cas
4.2.5. STAT3
5. The interaction between the EGFR and c-Src
5.1. c-Src has a synergistic effect in both EGF-induced cellular growth and tumorigenesis
5.2. The association between Src SH2 domain and the autophosphorylated EGFR
5.3. The events occurred accompanied with the formation of EGFR/c-Src complex
6. Cellular events that require the cooperation between EGF-activated EGFR and c-Src
6.1. EGFR endocytosis
6.2. EGF-induced cell migration
6.3. EGF-dependent cell survival
7. The interplay between EGFR and c-Src in the absence of EGF
7.1. Integrin activation
7.2. Membrane depolarization
7.3. Oxidative stress stimulation
7.4. Epoxyeicosatrienoic acid stimulation
7.5. GPCR activation
7.5.1. Gs and Gi
7.5.2. b-Arrestin
7.5.3. Gq
7.5.4. Gbg
8. The implication of EGFR/Src interaction in human tumors
9. Conclusions and future perspectives
10. Acknowledgements
11. References

1. ABSTRACT

EGF receptor (EGFR) and c-Src are the prototypes that individually represent the receptor and nonreceptor tyrosine kinases respectively. Accumulated evidence reveals the association between EGF-activated EGFR and c-Src that leads to activation of both kinases. Importantly, their mutual interaction is required for many EGFR-mediated cellular functions including proliferation, migration, survival and EGFR endocytosis. Interestingly, activation of c-Src and its association with transactivated EGFR is also observed in cells stimulated with non-EGF agonists. This review will not only discuss the structure, function and regulation of these two tyrosine kinases, but also will summarize our current knowledge of the molecular mechanisms depicting the cellular events that require their participation.