Integrins carbohydrate

Macromolecular complexes of proteins and carbohydrate present in the ECM serve not only as adhesive keeping cells in their correct positions but also facilitate control of cell activity by signalling through membrane proteins such as the integrin family of receptors. Glycoproteins are mainly protein with covalently attached carbohydrate whereas proteoglycans are predominantly complex carbohydrates secured on a protein framework. 

Stockl, J., Majdic, O., Rosenkranz, A., Fiebiger, E., Kniep, B., Stockinger, H., Knapp, W. Monoclonal antibodies to the carbohydrate structure Fewisx stimulate the adhesive activity of leukocyte integrin CDllb/CD18 (CR3, Mac-1, a, f)2) on human granulocytes. J Feukocyte Biol 53 (1993) 541-549. 

Recruitment of leukocytes is receptor-mediated. The products of inflammation, such as histamine, promote the immediate expression of P-selectin on endothelial cell surfaces. This receptor binds weakly to carbohydrate ligands on leukocyte surfaces and causes them to roll along the endothelial surface as bonds are made and broken. Cytokines from injured cells induce the expression of E-selectin on endothelial cells, which functions similarly to P-selectin. Cytokines also induce the expression of integrin ligands on endothelial cells, which further slow the movement of leukocytes. These weakly bound leukocytes are free to detach if not activated by chemokines produced in injured tissue. Activation increases the affinity of bound integrin receptors for ligands on the endothelial cell surface, firmly binding the leukocytes to the endothelium. 

Figure 14.1 Leukocyte transmigration. Expression of P- and E-selectins (and integrins) on the endothelial surface of damaged cells weakly binds leukocyte carbohydrate ligands, slowing and causing the leukocyte to roll over the endothelial surface, eventually holding the leukocyte in place.

In contrast to the high affinity biotin-(strept)avidin bonds, carbohydrate-L-selectin bonds with modest affinity stop white cells at vessel walls in the circulation. Numerous bonds to other surface (integrin) receptors then form between the white cell and vessel wall to sustain adhesion and enable subsequent movement into the surrounding tissue. On its initial arrest from the blood flow, the white cell can be subjected to forces of 100 pN in a time frame of milliseconds, which implies loading rates of lO -lO pN s . With this functional requirement in mind, we now examine recent tests of carbohydrate-L-selectin bonds under dynamic loading in probe tests. 

The selectins are a family of lectins that mediate the movement of leukocytes from the bloodstream into sites of inflammation. This multistep cascade proceeds by initial attachment leading to the rolling of leukoc)rtes along endothelial vasculature via selectin-carbohydrate interactions. Subsequent firm adhesion requires chemoattractant activation of leukocyte p2 integrins which mediate arrest through interaction with endothelial receptors. Leukocytes then extravasate between endothelial cells in the direction of chemoattractants as indicated in O Fig. 3 [42]. 

Figure 10-3 Influence of carbohydrates (A to D) and MOE (E) on integrin biology. See the text for a more detailed discussion.

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