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Glypican 3 increases IRS4 phosphorylation and stimulates Hepatocellular Carcinoma cell proliferation
Author(s) -
Ganapathy Ekambaram,
Khachatoorian Ronik,
French Samuel W
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.872.11
Subject(s) - glypican 3 , phosphorylation , cell growth , cancer research , microbiology and biotechnology , biology , chemistry , medicine , hepatocellular carcinoma , biochemistry
Hepatocellular carcinoma (HCC) is a common malignancy worldwide. Glypican 3 (GPC3) is one of the most over‐expressed proteins in HCC and is used as a diagnostic marker. Role of GPC3 in cell growth regulation is demonstrated by overgrowth and organ dysgenesis associated with altered gene expression; however the mechanism is not well characterized. To evaluate the effect of altering GPC3 levels, we used shRNA to examine the molecular and biologic effects of GPC3 suppression in HCC cells in vitro . Also, a mammalian expression vector expressing a Flag‐GPC3 fusion protein was used to understand the role of elevated levels of GPC3. Proteomic mass spectrometry was used to identify the cellular proteins in complex with Flag‐GPC3. We identified Insulin Receptor Substrate 4 (IRS4) as a GPC3 interaction partner. Over expression of GPC3 increased cell proliferation and IRS4 phosphorylation in HCC cells, while knock‐down of GPC3 inhibited cell proliferation and decreased IRS4 phosphorylation in HCC cells. These changes were not seen in 293 cells. IRS4 is associated with HCC tumor growth and cell proliferation. IRS4 is activated by tyrosine phosphorylation and mediates multiple signals following activation of insulin receptors by insulin like growth factor‐I (IGF‐I). Our results indicate that GPC3 modulates IRS4 phosphorylation to enhance HCC cell proliferation.