Smad Proteins and Hepatocyte Growth Factor Control Parallel Regulatory Pathways That Converge on β1-Integrin To Promote Normal Liver Development
Copyright policy )Smad Proteins and Hepatocyte Growth Factor Control Parallel Regulatory Pathways That Converge on β1-Integrin To Promote Normal Liver Development
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.
- The Ohio State University United States
- National Institutes of Health United States
- National Institute of Health Pakistan
- Temple University United States
- United States Department of Veterans Affairs United States
Heterozygote, Hepatocyte Growth Factor, Reverse Transcriptase Polymerase Chain Reaction, Integrin beta1, Blotting, Western, Active Transport, Cell Nucleus, Cadherins, Immunohistochemistry, DNA-Binding Proteins, Mice, Phenotype, Liver, Mutagenesis, Mutation, Cell Adhesion, Animals, Phosphorylation, Cell Division, Cells, Cultured, In Situ Hybridization
Heterozygote, Hepatocyte Growth Factor, Reverse Transcriptase Polymerase Chain Reaction, Integrin beta1, Blotting, Western, Active Transport, Cell Nucleus, Cadherins, Immunohistochemistry, DNA-Binding Proteins, Mice, Phenotype, Liver, Mutagenesis, Mutation, Cell Adhesion, Animals, Phosphorylation, Cell Division, Cells, Cultured, In Situ Hybridization
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