Journal Article Regulation of HGF-induced hepatocyte proliferation by the small GTPase Arf6 through the PIP2-producing enzyme PIP5K1A

Tsai, Meng-Tsz  ,  Katagiri, Naohiro  ,  Ohbayashi, Norihiko  ,  Iwasaki, Kenichi  ,  Ohkohchi, Nobuhiro  ,  Ding, Shih-Torng  ,  Kanaho, Yasunori  ,  Funakoshi, Yuji

7 ( 1 )  , p.9438 , 2017-08 , Nature Publishing Group
HGF and its receptor c-Met are critical molecules in various biological processes. Others and we have previously shown that the small GTPase Arf6 plays a pivotal role in HGF signaling in hepatocytes. However, the molecular mechanism of how Arf6 regulates HGF signaling is unclear. Here, we show that Arf6 plays an important role in HGF-stimulated hepatocyte proliferation and liver regeneration through the phosphatidylinositol 4,5-bisphosphate (PIP2)-producing enzyme PIP5K1A. We find that knockdown of Arf6 and PIP5K1A in HepG2 cells inhibits HGF-stimulated proliferation, Akt activation, and generation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) and its precursor PIP2. Interestingly, PIP5K1A is recruited to c-Met upon HGF stimulation in an Arf6 activity-dependent manner. Finally, we show that hepatocyte proliferation and liver regeneration after partial hepatectomy are suppressed in Pip5k1a knockout mice. These results provide insight into the molecular mechanism for HGF-stimulated hepatocyte proliferation and liver regeneration: Arf6 recruits PIP5K1A to c-Met and activates it upon HGF stimulation to produce PIP2 and subsequently PIP3, which in turn activates Akt to promote hepatocyte proliferation, thereby accelerating liver regeneration after liver injury.

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