H. William Schnaper, MD Professor Pediatrics Signal Transduction in fibrogenesis Curricula: Cancer Biology Cell Biology E-mail:   schnaper@northwestern.edu

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Our laboratory examines the signals that modulate fibrogenesis. This process is important in promoting normal healing but, when uncontrolled, leads to excessive scar formation such as occurs in chronic progressive cardiovascular or kidney disease. Our studies center upon the role of the Smad signal transduction pathway in extracellular matrix accumulation. We are investigating the mechanism(s) by which transforming growth factor (TGF)-ß stimulates collagen accumulation by the human kidney mesangial cells that are central to the scarring of the renal filter in disease states.

We have determined that the TGF-ß-specific Smad pathway is modulated by interaction with multiple additional signaling mechanisms, including those related to ERK MAP kinase, phosphatidyl inositol-3-kinase, protein kinase C and cytoskeletal rearrangement. Cross-talk among these pathways provides a complex milieu for the cellular regulation of fibrogenesis. Characterizing the precise patterns of interaction among signaling pathways that are usually studied in isolation offers our lab the opportunity to define unique events that determine tissue specificity.

Presently, we have two major projects in the lab.  In one, we are examining the role of Smad anchor for receptor activation (SARA) in regulating cell phenotype and function.  In the other, we are examining how cell interaction with the extracellular matrix leads to the activation of specific signaling pathways that promote fibrogenesis.  We recently reported that integrin-mediated, cell adhesion-dependent activation of focal adhesion kinase (FAK) plays an essential role in specific phosphorylations of the Smad3 molecule and in TGF-ß-stimulated collagen expression.

Publications:

Hayashida T, Wu M-H, Pierce A, Poncelet A-C, Varga J, Schnaper HW: TGF-ß-stimulated mesangial cell type I collagen expression requires adhesion-dependent, FAK Y397 phosphorylation-derived ERK MAP kinase activity. J Cell Sci 120: 4230-4240, 2007

Poncelet A-C, Schnaper HW, Tan R, Liu Y, Runyan CE: Cell phenotype-specific downregulation of Smad3 involves decreased gene activation as well as protein degradation. J Biol Chem 25:15534-15540, 2007.

Okano K, ,Bomsztyk K, Schnaper HW, Hayashida T:  RACK1 binds to Smad3 to modulate TGF-ß1-stimulated a2(I) collagen transcription in renal tubular epithelial cells. J Biol Chem 281:26196-26204, 2006

View Publications by Bill Schnaper listed in the National Library of Medicine (PubMed).

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