HEREGULIN DEGRADATION IN THE ABSENCE OF RAPID RECEPTOR-MEDIATED INTERNALIZATION

Heregulin receptors are unable to mediate the rapid internalization of bound ligand as demonstrated in cells transfected with chimeric or wi ld-type ErbB-2, -3, or -4 receptors (Baulida ct al., 1996, J. Biol. Ch em. 271, 5251-5257; Pinkas-Kramanski ct al., 1996, EMBO J. 15, 2452-24 67). This observation is now extended to include mammary carcinoma cel l lines (SK-BR-3 and MDA-543) which express endogenous ErbB-S and ErbB -3 receptors. Also, the fate of receptor-bound heregulin is examined. While receptor-bound heregulin is not rapidly internalized, the ligand is subject to a slow process of inactivation and degradation, which r equires heregulin incubation at 37 degrees C with cells that express h eregulin receptors. The degradation of heregulin is blocked to a signi ficant extent by chloroquine, an inhibitor of endosome fusion with lys osomes, indicating that heregulin is slowly internalized and degraded. However, this process is not sufficiently rapid to produce ligand-dep endent down-regulation of heregulin receptors. (C) 1997 Academic Press .