PHP14 regulates hepatic stellate cells migration in liver fibrosis via mediating TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway
- 411 Downloads
Hepatic fibrosis is characterized by the activation of hepatic stellate cells (HSCs). Migration of the activated HSCs to the site of injury is one of the key characteristics during the wound healing process. We have previously demonstrated that 14 kDa phosphohistidine phosphatase (PHP14) is involved in migration and lamellipodia formation of HSCs. However, the role of PHP14 in liver fibrosis remains unknown. In this study, we first assessed PHP14 expression and distribution in liver fibrotic tissues using western blot, immunohistochemistry, and double immunofluorescence staining. Next, we investigated the role of PHP14 in liver fibrosis and, more specifically, the migration of HSCs by Transwell assay and 3D collagen matrices assay. Finally, we explored the possible molecular mechanisms of the effects of PHP14 on these processes. Our results show that the PHP14 expression is up-regulated in fibrotic liver and mainly in HSCs. Importantly, TGF-β1 can induce PHP14 expression in HSCs accompanied with the activation of HSCs. Consistent with the previous study, PHP14 promotes HSCs migration, especially, promotes 3D floating collagen matrices contraction but inhibits stressed-released matrices contraction. Mechanistically, the PI3Kγ/AKT/Rac1 pathway is involved in migration regulated by PHP14. Moreover, PHP14 specifically mediates the TGF-β1 signaling to PI3Kγ/AKT pathway and regulates HSC migration, and thus participates in liver fibrosis. Our study identified the role of PHP14 in liver fibrosis, particularly HSC migration, and suggested a novel mediator of transducting TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway.
PHP14 is up-regulated in fibrotic liver and activated hepatic stellate cells.
The expression of PHP14 is induced by TGF-β1.
The migration of hepatic stellate cells is regulated by PHP14.
PHP14 is a mediator of TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway in hepatic stellate cells.
KeywordsPHP14 Hepatic stellate cell Migration PI3Kγ/AKT/Rac1 pathway Liver fibrosis
This study was supported by a grant from the Beijing Talents Fund (no. 2016000021469G227); the National Natural Science Foundation of China (no.81071973); Wang Bao-En Liver Fibrosis Foundation (no. 20100013); and the Rising Star Program from Beijing Friendship Hospital (no. yyqdkt201516).
Compliance with ethical standards
Competing financial interests
The authors declare that have no competing interests.
- 10.Xu A, Li X, Li S, Sun L, Wu S, Zhang B, Huang J (2016) A novel role for 14-kDa phosphohistidine phosphatase in lamellipodia formation. Cell Adhes Migr:1–8. https://doi.org/10.1080/19336918.2016.1268319
- 16.Lorenzini S, Bird TG, Boulter L, Bellamy C, Samuel K, Aucott R, Clayton E, Andreone P, Bernardi M, Golding M et al (2010) Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver. Gut 59:645–654CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Xue F, Janzen DM, Knecht DA (2010) Contribution of filopodia to cell migration: a mechanical link between protrusion and contraction. Int J Cell Biol 2010:507821Google Scholar
- 20.Okayama T, Kikuchi S, Ochiai T, Ikoma H, Kubota T, Ichikawa D, Fujiwara H, Okamoto K, Sakakura C, Sonoyama T et al (2008) Attenuated response to liver injury in moesin-deficient mice: impaired stellate cell migration and decreased fibrosis. Biochim Biophys Acta 1782:542–548CrossRefPubMedGoogle Scholar