Smad proteins and hepatocyte growth factor control parallel regulatory pathways that converge on beta1-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.
Weinstein
M
M
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20878, USA.
Monga
S P
SP
Liu
Y
Y
Brodie
S G
SG
Tang
Y
Y
Li
C
C
Mishra
L
L
Deng
C X
CX
D021581:Active Transport, Cell Nucleus; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002455:Cell Division; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006579:Heterozygote; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D019012:Integrin beta1 / Q000378:metabolism*; D008099:Liver / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D016296:Mutagenesis; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015820:Cadherins; D004268:DNA-Binding Proteins; D019012:Integrin beta1; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor