Novel mechanism for regulation of epidermal growth factor receptor endocytosis revealed by protein kinase A inhibition

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dc.contributor.authorSalazar, G
dc.contributor.authorGonzález, A
dc.date.accessioned2025-01-21T01:30:26Z
dc.date.available2025-01-21T01:30:26Z
dc.date.issued2002
dc.description.abstractCurrent 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 A-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 clown-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.
dc.fuente.origenWOS
dc.identifier.doi10.1091/mbc.01-08-0403
dc.identifier.issn1059-1524
dc.identifier.urihttps://doi.org/10.1091/mbc.01-08-0403
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/96758
dc.identifier.wosidWOS:000175812900020
dc.issue.numero5
dc.language.isoen
dc.pagina.final1693
dc.pagina.inicio1677
dc.revistaMolecular biology of the cell
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleNovel mechanism for regulation of epidermal growth factor receptor endocytosis revealed by protein kinase A inhibition
dc.typeartículo
dc.volumen13
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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