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Vol. 13, Issue 5, 1677-1693, May 2002
Departamento de Inmunología Clínica y
Reumatología, Facultad de Medicina. Centro de Regulación
Celular y Patología, Departamento de Biología Celular y
Molecular, Facultad de Ciencias Biológicas, Pontificia
Universidad Católica de Chile, and Millennium Institute for
Fundamental and Applied Biology, Santiago, Chile
Current models put forward that the epidermal growth factor
receptor (EGFR) is efficiently internalized via clathrin-coated pits
only in response to ligand-induced activation of its intrinsic tyrosine
kinase and is subsequently directed into a lysosomal-proteasomal degradation pathway by mechanisms that include receptor tyrosine phosphorylation and ubiquitylation. Herein, we report a novel mechanism of EGFR internalization that does not require ligand binding,
receptor kinase activity, or ubiquitylation and does not direct the
receptor into a degradative pathway. Inhibition of basal protein kinase
A (PKA) activity by H89 and the cell-permeable substrate peptide
Myr-PKI induced internalization of 40-60% unoccupied, inactive EGFR,
and its accumulation into early endosomes without affecting endocytosis
of transferrin and µ-opioid receptors. This effect was abrogated by
interfering with clathrin function. Thus, the predominant distribution
of inactive EGFR at the plasma membrane is not simply by default but
involves a PKA-dependent restrictive condition resulting in receptor
avoidance of endocytosis until it is stimulated by ligand. Furthermore,
PKA inhibition may contribute to ligand-induced EGFR endocytosis
because epidermal growth factor inhibited 26% of PKA basal
activity. On the other hand, H89 did not alter ligand-induced
internalization of EGFR but doubled its half-time of down-regulation by
retarding its segregation into degradative compartments, seemingly due
to a delay in the receptor tyrosine phosphorylation and ubiquitylation.
Our results reveal that PKA basal activity controls EGFR function at
two levels: 1) residence time of inactive EGFR at the cell surface by a
process of "endocytic evasion," modulating the accessibility of
receptors to stimuli; and 2) sorting events leading to the
down-regulation pathway of ligand-activated EGFR, determining the
length of its intracellular signaling. They add a new dimension to the
fine-tuning of EGFR function in response to cellular demands and cross
talk with other signaling receptors.
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