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Met, the Hepatocyte Growth Factor Receptor, Localizes to the Nucleus in Cells at Low Density

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: David L. Rimm, Department of Pathology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510. Phone: 203-737-4204; Fax: 203-737-5089; E-mail: david.rimm{at}yale.edu.

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 four unique antibodies. Cell fractionation reveals a 60-kDa band recognized by COOH-terminal Met antibodies that is present independent of hepatocyte growth factor treatment. Green fluorescent protein (GFP) fusion proteins of the cytoplasmic domain of Met transfected into HEK293 cells are found in the nucleus whereas 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. 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 in cells at low density. (Cancer Res 2006; 66(16): 7976-82)

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