Study of the Regulation of ErbB Signaling by Receptor-Mediated Endocytosis.

摘要

My proposal has envisioned a study of endocytic rate of EUFR in cells expressing different versions of erbE2. ErbB receptors are dimerized by their ligands, leading to receptor activation and internalization. internalized receptors are degraded in lysosorne, terminating the signal. The C-terminal region of EOFR contains endocytic motifs that regulate the internalization of EOFR. ErbB2 may also contain endocytic motifs. ErbB2 dimerizes with EUFR, and it may regulate the endocytosis rate of its dimerization partner. The presence of erbE2 may retard the internalization of EGFR, prolonging its presence on cell surface and potentiating its activation. I was able to show in transiently transfected BeLa cells that transient overexpression of erblB2 led to a decrease of endocytosis, measured indirectly by phosphorylation of brs 1. I was unable to develop a stable erbB2 overexpressing line, however. Several studies since the submission of my proposal supported the idea that erbB2 expression leads to a decrease in EGFR internalization (Wang et al., 1999; Worthylake et al., 1999). Another study showed that erbB2 overexpression in BT-20 cells led to prolonged downstream signaling by Raf- 1 and MAPK, compared with cells that expressed lower level of erbB2 (Zhang et al., 2002). These studies provided support to my hypothesis that erblB2 plays a regulatory role on EGFR signaling by modulating its internalization.