Novel Pathway to Down-Regulate ErbB Signaling in Mammary Epithelial Cells

摘要

Activation of tyrosine kinases plays a key role in cell proliferation, and ErbB receptor tyrosine kinases are specifically implicated in breast cancer. Biochemical studies have recently identified the proto-oncogene product Cbl as a negative regulator of EGF receptor and ErbB2. The Cbl-dependent negative regulation of ErbB receptors was associated with their ubiquitin modification and down-regulation from the cell surface. Based on these observations, this proposal is investigating the role of Cbl-mediated ubiquitination as a signal for targeting activated ErbB receptors to lysosomes where they undergo degradation. The work reported here has demonstrated that ubiquitin modification of EGFR is essential for its down-regulation. Furthermore, this modification is shown to be essential for EGFR trafficking between early and late endosome, while being dispensable for initial endocytosis. Further studies aim to establish the relative role of Cbl-dependent ubiqiuitinylation versus other endocytic motifs in ErbB receptor internalization, and dissect out components of the biochemical machinery that mediates ubiquitin-dependent lysosomal sorting of ErbB receptors. Elucidation of this novel pathway of ErbB receptor downregulation is likely to reveal novel targets to develop rational therapeutic agents for breast cancers with aberrant expression and/or activity of ErbB receptors.