Integrated analyses of biological functions of sugar chains : Glycomics

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To know biological functions of sugar chain by integrated analyses, we have identified target glycoproteins of specific glycosyltransferases as follows.GnT-V catalyses the synthesis of beta 1-6 GlcNAc branching which involves inn tumor metastasis and invasion. In this project, we identified matriptase as a target molecule of GnT-V, which can activate uPA, and HGF. Addition of betal-6 GlcNAc branching on matriptase brought prolonged degradation of these proteins, leading to tumor metastasis in nude mice experiments.Cadherin and integrin are target molecules for GnT-III which involves in the synthesis of bisecting GlcNAc structure. Bisecting GlcNAc inhibit further processing of N-glycan elongation via GnT-V or GnT-IV. In this project, biological functions of sugar chains on integrin and ECM interaction were clarified as a level of purified molecules. Cadherin/beta catenin system is also regulated by GnT-III. Phosphorylation of beta-catenin is suppressed by GnT-III and expression of e-cadherin is controlled by GnT-IIIFut8 involves in core fucosylation on N-glycans. To know physiological meaning of Fut8, we established Fut8 deficient mice. This mouse shows severe growth retardation and 70% of mice die within 3 days after birth. Interestingly, pathological analysis showed emphysema-like lesion in lung of the mice. The mechanism underlying this change is due to dys-regulation of TGF beta-receptor, leading to increases in MMP expression.