Molecular characterization of SH3 domain binding kinase 1 (SBK1) and its role in hepatic epidermal growth factor receptor (EGFR) signaling

Abstract

More than 1.5 billion people are suffering from liver disease globally. Although our knowledge on the liver disease has been improved in the past 40 years, most liver diseases are only managed but not cured. Many liver diseases will cause hepatic cirrhosis, which is the late-stage fibrosis of the liver. According to the World Health Organization, cirrhosis was the eleventh leading cause of death worldwide in 2019. The majority of liver cirrhosis patients end up with liver failure, and the only treatment is liver transplantation. However, just 30% of the transplantation need is fulfilled annually in Hong Kong. Liver regeneration is crucial for liver transplant patients and those who need to remove part of their liver due to fibrosis or tumor. Therefore, identifying a novel liver regeneration regulator is beneficial to develop new treatments to cure liver disease and speed up liver recovery. Our laboratory has been studying the authentic function of a novel protein called SH3-domain binding kinase 1 (SBK1) in the liver. Using a unique protein-protein interactions screening method, BioID, we have recently discovered that SBK1 might be involved in epidermal growth factor receptor (EGFR) signaling. Because EGFR is one of the major mediators of liver regeneration, we hypothesized that hepatic SBK1 might enhance EGFR signaling and promote liver cell proliferation. Our in vitro studies demonstrated that SBK1 delayed EGF-induced EGFR degradation by enhancing the destruction of Casitas B lymphoma (c-Cbl), a ubiquitin ligase that mediates EGFR degradation. Cytosolic SBK1 could be translocated to the nucleus, where it interacted and phosphorylated nuclear receptor subfamily 4 group A member 1 (Nur77) upon EGF stimulation. Consequently, overexpression of SBK1 enhanced Hepa 1-6 liver cell proliferation and induced hepatic hyperplasia in C57BL/6N mice. To study the effect of Sbk1 ablation on liver cell proliferation, 2/3 partial hepatectomy was performed in the liver-specific Sbk1 knockout (LSKO) mice. Abolishing hepatic Sbk1 showed cell cycle dysregulation and delayed liver regeneration. Hence, our study suggested that hepatic SBK1 functions as a positive EGFR regulator and directly enhances liver regeneration.