| First Author | Awuah PK | Year | 2013 |
| Journal | Am J Pathol | Volume | 182 |
| Issue | 5 | Pages | 1648-58 |
| PubMed ID | 23529017 | Mgi Jnum | J:196196 |
| Mgi Id | MGI:5486652 | Doi | 10.1016/j.ajpath.2013.01.047 |
| Citation | Awuah PK, et al. (2013) Role and Regulation of PDGFRalpha Signaling in Liver Development and Regeneration. Am J Pathol 182(5):1648-58 |
| abstractText | Aberrant platelet-derived growth factor receptor-alpha (PDGFRalpha) signaling is evident in a subset of hepatocellular cancers (HCCs). However, its role and regulation in hepatic physiology remains elusive. In the current study, we examined PDGFRalpha signaling in liver development and regeneration. We identified notable PDGFRalpha activation in hepatic morphogenesis that, when interrupted by PDGFRalpha-blocking antibody, led to decreased hepatoblast proliferation and survival in embryonic liver cultures. We also identified temporal PDGFRalpha overexpression, which is regulated by epidermal growth factor (EGF) and tumor necrosis factor alpha, and its activation at 3 to 24 hours after partial hepatectomy. Through generation of hepatocyte-specific PDGFRA knockout (KO) mice that lack an overt phenotype, we show that absent PDGFRalpha compromises extracelluar signal-regulated kinases and AKT activation 3 hours after partial hepatectomy, which, however, is alleviated by temporal compensatory increases in the EGF receptor (EGFR) and the hepatocyte growth factor receptor (Met) expression and activation along with rebound activation of extracellular signal-regulated kinases and AKT at 24 hours. These untimely increases in EGFR and Met allow for normal hepatocyte proliferation at 48 hours in KO, which, however, are aberrantly prolonged up to 72 hours. Intriguingly, such compensation also was visible in primary KO hepatocyte cultures but not in HCC cells after siRNA-mediated PDGFRalpha knockdown. Thus, temporal activation of PDGFRalpha in liver development is important in hepatic morphogenesis. In liver regeneration, despite increased signaling, PDGFRalpha is dispensable owing to EGFR and Met compensation, which is unique to normal hepatocytes but not HCC cells. |
