|Susan L. Bellis, Ph.D.
Associate Professor, Department of Medicine
Areas of Focus: The role of integrin receptors in human biology and disease.
The role of ras-directed integrin sialylation in tumorigenesis/metastasis. The ectopic expression of oncogenic ras in epithelial cells causes increased synthesis of ST6Gal I, a Golgi enzyme that adds sialic acid to glycoproteins. In turn, b1, but not b3 or b5, integrins, are hypersialylated. Cells with hypersialylated b1 integrins exhibit impaired binding to collagen (a b1 ligand), but not to vitronectin (a b3 or b5 ligand). Similar to cultured cells, human tumors with oncogenic ras express hypersialylated b1, but not b3, integrins. Our studies suggest that hypersialylation of b1 integrins may contribute to tumor cell invasiveness by changing cell preference for selected extracellular matrix components, as well as increasing cell motility.
Hyposialylation of b1 integrins mediates the increased adhesiveness of differentiated monocytic cells. Differentiating monocytes exhibit increased adhesiveness to the b1 integrin ligands, VCAM-1 and fibronectin. During differentiation, the activation of a PKC/ras/MAPK signaling cascade induces downregulation of ST6Gal I. In turn, b1 integrins become hyposialylated. Expression of hyposialylated integrins is temporally correlated with enhanced adhesion, and both hyposialylation and adhesion are blocked by inhibitors of PKC, ras, or MAPK. Importantly, the enzymatic de-sialylation of purified b1 integrins significantly enhances fibronectin binding, suggesting that sialic acids directly modulate integrin function. We hypothesize that the increased binding activity of hyposialylated integrins contributes to the trafficking of monocytes to inflammatory sites.
Integrin-mediated adhesion of osteoblasts to implant materials. Clinical studies suggest that the implant material, hydroxyapatite, promotes better bone formation at the implant site than metals such as titanium. To better understand this phenomenon, we have developed an in vitro cell culture system that models the in vivo cell/implant interaction. In our system, discs made of biomaterials are coated with serum to recapitulate the coating of implants with blood that happens in vivo. We find that hydroxyapatite, as compared with titanium, adsorbs substantially more serum components that are ligands for integrin receptors. In turn, the higher concentration of integrin ligands promotes integrin-dependent adhesion of osteoblasts to hydroxyapatite. These studies suggest a molecular mechanism for the enhanced bone formation observed in vivo with hydroxyapatite-coated implants.