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Molecular and Cellular Biology, August 2001, p. 5122-5131, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5122-5131.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Smad Proteins and Hepatocyte Growth Factor Control Parallel Regulatory Pathways That Converge on beta 1-Integrin To Promote Normal Liver Development

Michael Weinstein,1,2 Satdarshan P. S. Monga,3,dagger Ye Liu,2 Steven G. Brodie,1 Yi Tang,3 Cuiling Li,1 Lopa Mishra,3,* and Chu-Xia Deng1,*

Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 208781; Department of Molecular Genetics and Molecular, Cellular, and Developmental Biology Program, Ohio State University, Columbus, Ohio 432102; and Laboratory of Gastrointestinal/Developmental Molecular Biology, Fels Cancer Institute, Temple University, Philadelphia, Pennsylvania 19140, and Department of Veterans' Affairs, Washington, D.C. 204223

Received 2 November 2000/Returned for modification 19 December 2000/Accepted 3 May 2001

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 beta 1-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 beta 1-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.

* Corresponding author. Mailing address for Chu-Xia Deng: Genetics of Development and Disease Branch, Building 10, Room 9N105, NIDDK, NIH, Bethesda, MD, 20878. Phone: (301) 435-2239. Fax: (301) 480-1135. E-mail: chuxiad{at}bdg10.niddk.nih.gov. Mailing address for Lopa Mishra: Fels Institute for Cancer Research and Molecular Biology, 3307 North Broad St., Philadelphia, PA 19140. Phone: (215) 707-0105. Fax: (215) 707-2102. E-mail: lmishra{at}unix.temple.edu.

dagger Present address: University of Pittsburgh, School of Medicine, Department of Pathology, Pittsburgh, PA 15261.

Molecular and Cellular Biology, August 2001, p. 5122-5131, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.5122-5131.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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