Tyrosine Kinases / Adaptors

The epidermal growth factor (EGF) receptor is a transmembrane tyrosine kinase that belongs to the HER/ErbB protein family. Ligand binding results in receptor dimerization, autophosphorylation, activation of downstream signaling, internalization, and lysosomal degradation (1,2). Phosphorylation of EGF receptor (EGFR) at Tyr845 in the kinase domain is implicated in stabilizing the activation loop, maintaining the active state enzyme, and providing a binding surface for substrate proteins (3,4). c-Src is involved in phosphorylation of EGFR at Tyr845 (5). The SH2 domain of PLCγ binds at phospho-Tyr992, resulting in activation of PLCγ-mediated downstream signaling (6). Phosphorylation of EGFR at Tyr1045 creates a major docking site for the adaptor protein c-Cbl, leading to receptor ubiquitination and degradation following EGFR activation (7,8). The GRB2 adaptor protein binds activated EGFR at phospho-Tyr1068 (9). A pair of phosphorylated EGFR residues (Tyr1148 and Tyr1173) provide a docking site for the Shc scaffold protein, with both sites involved in MAP kinase signaling activation (2). Phosphorylation of EGFR at specific serine and threonine residues attenuates EGFR kinase activity. EGFR carboxy-terminal residues Ser1046 and Ser1047 are phosphorylated by CaM kinase II; mutation of either of these serines results in upregulated EGFR tyrosine autophosphorylation (10).

Thr669 is a major phosphorylation site on EGF receptor after EGF stimulation. It is phosphorylated by p38 MAP kinase (11). Phosphorylation of the EGF receptor at Thr669 may be involved in regulation of ligand induced receptor internalization by interacting with downstream specific EGF receptor tyrosine kinase substrate(s) (11).

1. Hackel, P.O. et al. (1999) Curr Opin Cell Biol 11, 184-9.
2. Zwick, E. et al. (1999) Trends Pharmacol Sci 20, 408-12.
3. Cooper, J.A. and Howell, B. (1993) Cell 73, 1051-4.
4. Hubbard, S.R. et al. (1994) Nature 372, 746-54.
5. Biscardi, J.S. et al. (1999) J Biol Chem 274, 8335-43.
6. Emlet, D.R. et al. (1997) J Biol Chem 272, 4079-86.
7. Levkowitz, G. et al. (1999) Mol Cell 4, 1029-40.
8. Ettenberg, S.A. et al. (1999) Oncogene 18, 1855-66.
9. Rojas, M. et al. (1996) J Biol Chem 271, 27456-61.
10. Feinmesser, R.L. et al. (1999) J Biol Chem 274, 16168-73.
11. Winograd-Katz, S.E. and Levitzki, A. (2006) Oncogene 25, 7381-7390.

• Nishimura, M. et al. (2009) Mol Cell Biol 29, 5529-39. Applications: Western Blotting

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Phospho-EGF Receptor (Thr669) Antibody

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