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A more recent version of this article appeared on May 1, 2002
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Submitted on August 13, 2001
Revised on December 20, 2001
Accepted on January 24, 2002
1 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 MIFAB, Santiago, Chile
* Corresponding author. E-mail address: agonzara{at}med.puc.cl.
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. Here, 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 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 since EGF inhibited 26% of its 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; 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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