| pubmed-article:12006662 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:12006662 | lifeskim:mentions | umls-concept:C0034802 | lld:lifeskim |
| pubmed-article:12006662 | lifeskim:mentions | umls-concept:C0014139 | lld:lifeskim |
| pubmed-article:12006662 | lifeskim:mentions | umls-concept:C0010531 | lld:lifeskim |
| pubmed-article:12006662 | lifeskim:mentions | umls-concept:C0021467 | lld:lifeskim |
| pubmed-article:12006662 | lifeskim:mentions | umls-concept:C0021469 | lld:lifeskim |
| pubmed-article:12006662 | lifeskim:mentions | umls-concept:C0851285 | lld:lifeskim |
| pubmed-article:12006662 | lifeskim:mentions | umls-concept:C0679622 | lld:lifeskim |
| pubmed-article:12006662 | lifeskim:mentions | umls-concept:C0205314 | lld:lifeskim |
| pubmed-article:12006662 | lifeskim:mentions | umls-concept:C0441712 | lld:lifeskim |
| pubmed-article:12006662 | pubmed:issue | 5 | lld:pubmed |
| pubmed-article:12006662 | pubmed:dateCreated | 2002-5-13 | lld:pubmed |
| pubmed-article:12006662 | pubmed:abstractText | 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 mu-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. | lld:pubmed |
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| pubmed-article:12006662 | pubmed:language | eng | lld:pubmed |
| pubmed-article:12006662 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:12006662 | pubmed:citationSubset | IM | lld:pubmed |
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