Met Nuclear Localization and Signaling in Breast Cancer
Annual summary rept. 2 Apr 2005-1 Apr 2006
YALE UNIV NEW HAVEN CT
Pagination or Media Count:
Some breast cancer cases in our previous immunohistochemical studies show Met expression in the nucleus. Given nuclear localization of other receptor tyrosine kinases, we proceeded to investigate Met. Nuclear Met is seen in numerous cell lines and in germinal regions of many tissues using 4 unique antibodies. Cell fractionation reveals a 60kDa band recognized by C-terminal Met antibodies that is present independent of HGF treatment. GFP fusion proteins of the cytoplasmic domain of Met transfected into HEK293 cells are found in the nucleus while the full length Met-GFP fusion is membranous. Further deletions of the Met-GFP fusions identify a region of the juxtamembrane domain required for nuclear translocation. In a CaCo2 cell line model for epithelial maturation, we find that Met is initially nuclear, and then becomes membranous, after confluence. Nuclear translocation can then be induced by wounding the cell monolayer. This work suggests processing of the Met receptor, analogous to ErbB4, resulting in the release of the cytoplasmic domain and its translocation to the nucleus during stages of cell cell growth and proliferation.
- Anatomy and Physiology
- Medicine and Medical Research