Four heterodimers, namely a1b1, a2b1, a10b1 and a,11b1 form a structurally and functionally unique subgroup inside the integrin family. All four receptors bind to a variety of collagen subtypes and in most cell types they mediate direct interactions with collagen. Our observations indicate that some cells can concomitantly express the four collagen receptors suggesting that the receptors may have individual biological functions. The four collagen receptors share the common b1 subunit and their a subunits contain a specific collagen binding domain, termed the aI domain. We have been able to produce the four aI domains as recombinant proteins in E. coli and develop a solid -phase assay to test their binding specificity to diffe rent collagen subtypes. Furthermore, we have established CHO cell lines that express a1b1, a2b1, or a10b1 as their only collagen receptor. Our results indicate that a2b1 is the best receptor for fibril-forming collagen subtypes (I, II, III) and collagen fib rils. Integrins a1b1 and a10b1 seem to prefer network (IV) and beaded-filament (VI) forming collagens. Integrin a11b1 has similar binding preferences as a2b1 but its approximated avidity is remarkably weaker. Molecular modeling and mutation analysis has revealed some critical amino acids that participate in the determination of binding specificity. In addition to differences in the specificity of ligand recognition, collagen receptor integrins generate distinct cellular signals. Our previous studies have indicated that a2b1 integrin is an activator of type I collagen, collagenase -1 and -3 gene expression, whereas a1b1 seems to inhibit collagen production. More recently, we have shown that a2b1 may activate protein phosphatase 2A (PP2A) and subsequently dephosphorylate Akt-kinase. These observations support the earlier suggestions that in mesenchymal cells that are in contact with fibrillar collagen a2b1 inhibits cell proliferation and survival, whereas a1b1 may promote cell growth. We have previously shown that the effec t of a2b1 on collagen and collagenase expression is mediated by p38 MAP-kinase. Our recent data suggest that mechanical stress inside three-dimensional collagen gels is mediated by a2b1 and this plays critical role in the activation of p38. Genetical evidence about different biological roles of the collagen receptor integrins has been searched in knock-out mice. The a1 null mouse has been available for several years. It is viable but in functional assays it has been possible to confirm some of the a1b1 related functions, that have been earlier suggested in cell culture assays. For example, we have been able to show that a1b1 integrin is a negative feed-back regulator of collagen synthesis in the mouse skin. Furthermore, a1b1 seems to be important for the proliferation of bone marrow mesenchymal stem cells and the healing of bone fractures is impaired in a1 knock-out mice. To conclude, human cells express four structurally very similar integrin-type collagen receptors. A more detailed analysis has indicated that they have specific differences in their ligand recognition and signaling functions.

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