Future Directions

It has become clear that cell-cell and cell-substrate interactions mediated through adhesion molecules and their corresponding receptors play critical roles in cellular functions including growth, activation, differentiation, and death. One of the challenges facing researchers will be to define the molecular mechanisms triggered by the interaction between attachment factors and cell surface receptors that regulate cellular function. Recent advances in molecular biology have provided powerful tools by which to identify both extracellular and intracellular components of these complex signaling systems. Soluble, chimeric proteins containing the extracellular regions of attachment factors and cell surface receptors have been used to identify and clone novel interacting partners, to define domains and individual residues that participate in binding, and to examine the biological role of the attachment factor-cell surface receptor interaction. In addition to being a tool for studying the biochemistry and biology of attachment factor-cell surface interactions, soluble chimeric proteins are also being pursued as novel drug candidates. The ability of soluble, chimeric proteins to mimic their native counterparts may allow for the generation of effective biological-based drugs that can modulate protein-protein, or cell-cell interactions and their downstream signaling events.

In addition to defining extracellular interations, the development of powerful molecular biology approaches has provided novel methods by which to identify proteinprotein interactions that occur inside cells. The yeast two-hybrid system has been used to identify signaling proteins that interact with the cytoplasmic domains of various attachment factor cell surface receptors. This system has been used to identify several proteins that play important roles in integrin function, including the cytoskeletal protein filamin (27,28), cytohesin 1 (208), integrin-linked kinase (209), and f3 endonexin (210). This system will continue to provide a means of identifying molecules that interact with the cytoplasmic domain of attachment factor cell surface receptors and participate in attachment factor-cell surface receptor interactions. These approaches, together with the current explosion in the identification and cloning of novel attachment factor receptors through use of genomic-based bioinformatics, will provide an exciting opportunity for interface between attachment factor biologists, molecular and cell biologists investigating cell signaling, and bioinformaticians in the development of the biology of cell attachment.

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