In contrast, Gßc interacts with both the N-terminal pleckstrin homology domain and the catalytic domain and can reverse inhibition of PLCb2 by c-synuclein. This reversal is not due to competition of c-synuclein binding by Gßc since csynuclein binds well to both PLCb2 and PLCb2-Gßc. Instead, our data suggest that ternary complexes can form. We hypothesize that the mechanism through which Gßc activates the enzyme does not allow for c-synuclein inhibition. Since Gßc and c-synuclein inversely affect product release,, it is possible that the conformational changes associated with product release which are promoted by Gßc are preserved in the presence of c-synuclein, and that displacement of c-synuclein may not be required for reversal of inhibition. Thus, Gßc is a more potent activator of PLCb2- c-synuclein than isolated PLCb2. More studies are needed to understand the conformational changes associated with product release. Regardless of the mechanism, inhibition of PLCb2 by c-synuclein may not have significant cellular effects since the basal activity of PLCb2 is low. However, the ability of Gaqand Gßc to activate PLCb2 while simultaneously reversing inhibition may lead to an apparently more robust calcium signals. Sialic acids are widely distributed across species, from ICI 182780 Estrogen Receptor inhibitor viruses and microorganisms to higher animals, including all mammals. They usually exist as glycoconjugate-bound forms, and the bound sialic acids can modify the conformation, intermolecular interactions, and half lives of the glycoconjugates. Many reports have shown that the sialylation level of glycoconjugates changes during physiological and pathological processes such as cell growth, differentiation, immune responses, and tumorigenesis. For example, upon malignant transformation, the amounts and types of sialic acids on cell-surface glycoproteins or glycolipids are altered, although the physiological meanings of these changes have not been fully elucidated. As expected from the effects on glycoconjugates of binding sialic acids, the removal of sialic acid moieties also affects biological processes. Sialidases are alpha ketosidases that catalyze the removal of sialic acids from glycoconjugates. In mammalian cells, there are four sialidases that differ in their subcellular localizations, substrate preferences, optimum pH, and sensitivity to inhibitors. These distinct characteristics may reflect the sialidases’ different physiological roles. Of the four mammalian sialidases, NEU3 localizes to the membrane fraction of cells and shows a strong preference for gangliosides as substrates. We and others have shown that NEU3 can modulate biological processes, including neuronal differentiation, T-cell activation, monocyte differentiation, cell adhesion and motility, and the onset of a diabetic phenotype. In addition, we demonstrated that human NEU3 is upregulated in terms of both enzymatic activity and mRNA level in many human cancers, including colon, renal, prostate, and ovarian cancers. NEU3 appears to be indispensable for the survival of cancer cells, since small interfering RNA-mediated knock down of NEU3 in cancer cell lines leads to decreased epidermal growth factor receptor phosphorylation and the suppression of Ras and extracellular signal-regulated kinase activation, which in turn results in apoptosis of the cells. Interestingly, NEU3 knock down did not induce apoptosis in similarly treated primary cultures of fibroblasts or keratinocytes. Human NEU3-expressing transgenic mice, whose colon mucosa had 33-times more sialidase activity than that of wild-type mice, showed enhanced formations of aberrant crypt foci in response to the colonogenic carcinogen, azoxymethane.