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Vol. 12, Issue 6, 1897-1910, June 2001
Department of Pathology, Division of Cell Biology and Immunology,
University of Utah, Salt Lake City, Utah 84132
Ligand activation of the epidermal growth factor receptor (EGFR)
leads to its rapid internalization and eventual delivery to lysosomes.
This process is thought to be a mechanism to attenuate signaling, but
signals could potentially be generated after endocytosis. To directly
evaluate EGFR signaling during receptor trafficking, we developed a
technique to rapidly and selectively isolate internalized EGFR and
associated molecules with the use of reversibly biotinylated anti-EGFR
antibodies. In addition, we developed antibodies specific to
tyrosine-phosphorylated EGFR. With the use of a combination of
fluorescence imaging and affinity precipitation approaches, we
evaluated the state of EGFR activation and substrate association during
trafficking in epithelial cells. We found that after internalization, EGFR remained active in the early endosomes. However, receptors were
inactivated before degradation, apparently due to ligand removal from
endosomes. Adapter molecules, such as Shc, were associated with EGFR
both at the cell surface and within endosomes. Some molecules, such as
Grb2, were primarily found associated with surface EGFR, whereas
others, such as Eps8, were found only with intracellular receptors.
During the inactivation phase, c-Cbl became EGFR associated, consistent
with its postulated role in receptor attenuation. We conclude that the
association of the EGFR with different proteins is compartment
specific. In addition, ligand loss is the proximal cause of EGFR
inactivation. Thus, regulated trafficking could potentially influence
the pattern as well as the duration of signal transduction.
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 J. M. Haugh Localization of Receptor-Mediated Signal Transduction Pathways: The Inside Story Mol. Interv., September 1, 2002; 2(5): 292 - 307. [Abstract] [Full Text] [PDF]
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