Novel functions of individual epidermal growth factor receptor autophosphorylation sites in receptor regulation and signal transduction

David R Emlet, Thomas Jefferson University

Abstract

The epidermal growth factor receptor (EGFR) is the prototypic member of the receptor protein tyrosine kinase (RPTK) family of proteins, and it plays an essential role in both normal and neoplastic signal transduction in many cell types. Critical for the specificity of signaling from the EGFR are its sites of tyrosine autophosphorylation, as they mediate the association and subsequent activation of downstream effector molecules that contain src homology-2 (SH2) domains. This work has focused on gaining a better understanding of the function of these autophosphorylation sites. To accomplish this goal, we have generated glutathione S-transferase (GST) SH2 domain fusion protein constructs, tyrosine to phenylalanine (Y-F) EGFR autophosphorylation site mutants, and EGFR autophosphorylation site phospho-specific antibodies. Utilization of these reagents has revealed novel roles for the EGFR autophosphorylation site in signal transduction and receptor regulation. We have discovered that phosphorylation of EGFR tyrosine 992 (Y992) identifies a subset of receptors that likely constitutes the major population of signaling receptors. Also, we have uncovered additional evidence to suggest that Y992 plays a direct role in the overall signaling of the EGFR. Furthermore, we have discovered a novel role for a second autophosphorylation site, Y1068, in mediating the EGFR association and phosphorylation of phospholipase Cγ (PLCγ). We have also identified the sites on the EGFR that differentially affect the phosphorylation of the signal transducer and activators of transcription (STAT) family members 1, 3 and 5. Lastly, we have discovered numerous correlations between the EGFR mediated phosphorylation of PLCγ, and the EGFR mediated phosphorylation of STATs 1 and 3, implicating a potential role of PLCγ in the EGFR activation of STAT 1 and STAT 3.^

Subject Area

Biology, Molecular

Recommended Citation

David R Emlet, "Novel functions of individual epidermal growth factor receptor autophosphorylation sites in receptor regulation and signal transduction" (January 1, 2003). ETD Collection for Thomas Jefferson University. Paper AAIDP18520.
http://jdc.jefferson.edu/dissertations/AAIDP18520

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