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Regulation of HGF-induced hepatocyte proliferation by the small GTPase Arf6 through the PIP5K1A

Scientific Reports, ISSN: 2045-2322, Vol: 7, Issue: 1, Page: 9438
2017
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Article Description

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 (PIP)-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 (PIP) and its precursor PIP. 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 PIP and subsequently PIP, which in turn activates Akt to promote hepatocyte proliferation, thereby accelerating liver regeneration after liver injury.

Bibliographic Details

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

Springer Science and Business Media LLC

Multidisciplinary

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