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Regulation of liver growth by Glypican 3, CD81, Hedgehog, and Hhex
Author(s) -
Bhave Vishakha,
Mars Wendy,
Donthamsetty Shashikiran,
Luo Jianhua,
Bowen William,
Michalopoulos George
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.872.3
Subject(s) - microbiology and biotechnology , repressor , biology , nuclear receptor , hedgehog , hepatocyte , transcription factor , signal transduction , chemistry , biochemistry , gene , in vitro
Previous studies from our lab have shown Glypican 3 (GPC3) as a negative regulator of growth. CD81 was found to be a binding partner for GPC3 and its expression and co‐localization with GPC3 increased at the end of hepatocyte proliferation. However, the mechanisms through which these two molecules might regulate liver regeneration are not known. We tested the hypothesis that GPC3 downregulates Hedgehog (HH) signaling pathway by competing with Patched‐1 for HH binding. We found decreased GPC3‐Indian HH binding at peak proliferation in mice followed by decrease in Glioblastoma 1 (GLI1) protein. We performed a yeast two‐hybrid assay and identified Hemopoietically expressed homeobox (Hhex, a known transcriptional repressor) as a binding partner for CD81. We tested the hypothesis that Hhex binding to CD81 keeps it outside the nucleus. However when GPC3 binds to CD81, CD81‐Hhex binding decreases, resulting in nuclear translocation of Hhex and transcriptional repression. In support of this, we saw decreased GPC3‐CD81 binding at hepatocyte proliferation peak, increased CD81‐Hhex binding, and decreased nuclear Hhex. GPC3 transgenic mice were used as an additional tool to test our hypothesis. Overall, our data suggest that GPC3 downregulates cell proliferation by: 1) binding to HH and downregulating HH pathway; and 2) binding with CD81 making it unavailable to bind to Hhex and causing nuclear translocation of Hhex.