Synergistic antiproliferative and apoptotic effects induced by epidermal growth factor receptor and protein kinase a inhibitors in human prostatic cancer cell lines

2003 ◽  
Vol 106 (1) ◽  
pp. 116-124 ◽  
Author(s):  
Murielle Mimeault ◽  
Nicole Pommery ◽  
Jean-Pierre Hénichart
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Protein Kinase A ◽  
Prostatic Cancer ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Apoptotic Effects ◽  
Kinase A

scholarly journals Novel Mechanism for Regulation of Epidermal Growth Factor Receptor Endocytosis Revealed by Protein Kinase A Inhibition

2002 ◽  
Vol 13 (5) ◽  
pp. 1677-1693 ◽  
Author(s):  
Gloria Salazar ◽  
Alfonso González
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Protein Kinase A ◽  
Tyrosine Phosphorylation ◽  
Growth Factor Receptor ◽  
Basal Activity ◽  
Epidermal Growth ◽  
Kinase A

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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