CADHERIN ADHESION AND CELL DIFFERENTIATION

Lankenau Institute For Medical Research, Wynnewood PA

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Abstract

Cadherins and catenins are multifunctional proteins that promote specific cell-cell adhesion and intracellular signaling. They have been shown to modulate diverse cellular processes, including cytoskeleton organization, extracellular matrix adhesion, migration, cell polarity, proliferation, apoptosis, and differentiation. Cadherins form a superfamily of Ca++-dependent transmembrane glycoproteins. They are important morphogens whose expression is regulated spatiotemporally during embryogenesis. They also are widely expressed in adults. The cadherin intracellular domain is highly conserved and interacts with several proteins, collectively termed catenins. Catenins link cadherins to the actin cytoskeleton, which strengthens cadherin adhesion and organizes the cytoskeleton. Beta-catenin functions also as a signaling molecule in the Wnt/Wng pathway, where it alters transcription, and subsequently cell behavior. Germ line deletion of cadherin or catenin function in mice results in embryonic death or tissue abnormalities. In human adults, alterations in cadherin of catenin expression are frequently observed in tumors. Whereas the mechanism of cadherin adhesion and signaling via beta-catenin is well understood, less is known about how cadherin adhesion regulates cell behavior. We postulate that cadherin adhesion alters gene transcription, and present preliminary data showing that N-cadherin adhesion up- regulates transcription of the muscle specific transcription factor myogenin in differentiating skeletal muscle cells. The goal of the proposed work is to define the cadhern responsive regulatory element(s) in the myogenin promoter, and to establish the mechanism for its enhanced activity. The work will expand our understanding of how cadherin adhesion affects cell behavior, and promotes skeletal myogenesis.