The Src family kinases: distinct functions of c-Src, Yes, and Fyn in the liver

Abstract

Abstract:The Src family kinases Yes, Fyn, and c-Src play a pivotal role in regulating diverse liver functions such as bile flow, proteolysis, apoptosis, and proliferation and are regulated by anisoosmotic cell volume changes, death receptor ligands, and bile acids. For example, cell swelling leads to an integrin-sensed and focal adhesion kinase-mediated activation of c-Src-triggering choleresis, proteolysis inhibition, regulatory volume decrease via p38 MAPK and proliferation via the activation of the epidermal growth factor receptor and extracellular regulated kinases 1 and 2. In contrast, hepatocyte shrinkage generates an almost instantaneous oxidative stress response that triggers the activation of c-Jun N-terminal kinase and the Src family kinases Fyn and Yes. Whereas Fyn activation mediates cholestasis, Yes triggers CD95 activation and apoptosis. This review will discuss the role of Src family kinases in the regulation of liver function with emphasis on their role in osmo-signaling and bile acid signaling.

TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro

“…Stimulation of TGR5 has been shown to trigger RNOS formation in cholangiocytes (this study), astrocytes as well as in an oesophageal adenocarcinoma cell line 38 70. Oxidative stress in turn promotes phosphorylation of tyrosine kinases, such as members of the Src family, through inhibition of protein phosphatases 54 71 72. Activated cSrc can stimulate the metalloproteinase ADAM17, thereby increasing shedding of EGFR ligands 73.…”

“…Stimulation of TGR5 can promote the formation of RNOS,38 which in turn can activate Src kinases 54. Incubation of TGR5-WT and TGR5-KO cholangiocytes with TC acid, TLC acid and the TGR5 agonist (Ago-R) induced a significant increase in RNOS formation only in WT-derived but not in TGR5-KO-derived cells (n=4–9, figure 6A, B).…”

The calcium-activated potassium channel KCa3.1 is an important modulator of hepatic injury

“…Our view is encouraged by recent studies in a model of alveolar epithelial repair in which a complementary role of the swelling activated β 1 -integrin and KCa3.1 was described 50 . This again points to the importance of KCa3.1 in hepatocyte volume homeostasis and differentiated Src family kinase activation 51 as it might protect hepatocytes from an overwhelming cell swelling in the context of hepatocyte proliferation.…”

4-Hydroxynonenal activates Src through a non-canonical pathway that involves EGFR/PTP1B

“…Src mediates multiple cell signaling pathways [64] and is involved in cancers, inflammation, immune response, and many other pathophysiological processes [65–68]. Src activation in response to oxidative stress has been well established [68–71], and the underlying mechanism involves oxidative modification of cysteine residuals in Src.…”