Smad Proteins and Hepatocyte Growth Factor Control Parallel Regulatory Pathways That Converge on β1-Integrin To Promote Normal Liver Development

Abstract

Smads serve as intracellular mediators of transforming growth factor beta (TGF-beta) signaling. After phosphorylation by activated type I TGF-beta receptors, Smad proteins translocate to the nucleus, where they serve as transcription factors and increase or decrease expression of TGF-beta target genes. Mice lacking one copy each of Smad2 and Smad3 suffered midgestation lethality due to liver hypoplasia and anemia, suggesting essential dosage requirements of TGF-beta signal components. This is likely due to abnormal adhesive properties of the mutant hepatocytes, which may result from a decrease in the level of the beta1-integrin and abnormal processing and localization of E-cadherin. Culture of mutant livers in vitro revealed the existence of a parallel developmental pathway mediated by hepatocyte growth factor (HGF), which could rescue the mutant phenotype independent of Smad activation. These pathways merge at the beta1-integrin, the level of which was increased by HGF in the cultured mutant livers. HGF treatment reversed the defects in cell proliferation and hepatic architecture in the Smad2(+/-); Smad3(+/-) livers.

RING finger-dependent ubiquitination by PRAJA is dependent on TGF-β and potentially defines the functional status of the tumor suppressor ELF

“…For these studies, we utilized a ELF-specific polyclonal antibody (VA-1) (Mishra et al, 1998(Mishra et al, , 1999Tang et al, 2002) that recognizes N-terminal sequence unique for ELF spectrin. Confocal experiments have shown ELF expression at the apical, canalicular surface of hepatocytes (Weinstein et al, 2001). TGF-b levels during PH have been described before.…”

“…Defective liver development with loss of gastrointestinal epithelial cell shape and polarity is also seen in elf À/À homozygotes, Smad2 þ /À and Smad3 þ /À double heterozygous mice. Strikingly, hepatocellular carcinoma (HCC) is seen in elf þ /À heterozygotes (Weinstein et al, 2001). ELF therefore is one of the few adaptor proteins that acts as a tumor suppressor.…”

Endodermal and mesenchymal cross talk: a crossroad for the maturation of foregut organs

“…[6][7][8]. Endothelial cells (ECs) have been shown to influence IHBD development by communicating, via paracrine mechanisms, with hepatocytes in the region of the portal mesenchyme (9).…”

Genetic signatures shared in embryonic liver development and liver cancer define prognostically relevant subgroups in HCC

“…Recently, several studies on liver embryonic development have established the concept that the genetic programs controlling liver development are often deregulated in liver cancer. Signaling transductory pathways including Wnt-signaling pathway [4][5][6][7][8][9], TGF-β signaling pathway [10][11][12], MAPK signaling pathway [13,14], Jak-STAT signaling pathway [15,16], Notch signaling pathway [17,18], and the Hedgehog signaling pathway [19,20] have been reported to play important roles in hepatoblast proliferation and differentiation during embryonic development, as well as in hepatocarcinogenesis. Since many biological mechanisms such as cell cycle control, growth and proliferation are essential to both embryonic development and cancer de-differentiation, this may not be completely surprising.…”