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J. Biol. Chem., Vol. 269, Issue 15, 11011-11017, Apr, 1994

Defective asialoglycoprotein receptor endocytosis mediated by tyrosine kinase inhibitors. Requirement for a tyrosine in the receptor internalization signal

RJ Fallon, M Danaher, RL Saylors and A Saxena
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.

Regulated endocytosis by growth factor receptors requires intact receptor-associated tyrosine kinase activity. To determine whether a similar requirement exists for the asialoglycoprotein (ASGP) receptor which lacks intrinsic tyrosine kinase activity and participates in constitutive endocytosis, we examined the effect of three tyrosine kinase inhibitors, tyrphostin, genistein, and staurosporine, on receptor-mediated endocytosis in the human hepatoma line HepG2. These compounds inhibited early receptor internalization from the plasma membrane to internal protease-resistant sites in a concentration- dependent manner. This effect correlated with their inhibition of tyrosine phosphorylation of the ASGP receptor in vitro. Receptor trafficking subsequent to receptor internalization was unaffected. Endocytosis of another constitutively internalized protein, the transferrin receptor, was also inhibited by these compounds. In contrast, pinocytosis of the fluid-phase marker Lucifer yellow was not inhibited. The tyrosine kinase inhibitors also decreased the endocytic rate of transfected ASGP receptor H1 subunit in SK-Hep-1 cells. Therefore an intact ASGP receptor heterooligomeric complex is not required for this effect. Mutation of the single cytoplasmic tyrosine at position 5 of the H1 subunit to phenylalanine produced an ASGP receptor which was endocytosed regardless of treatment with the tyrosine kinase inhibitors. We conclude that tyrosine kinase activity modulates the rate of receptor endocytosis at a point early in the internalization process.
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