Sen-itiroh Hakomori

I have developed technologies for isolation and structural characterization of glycosphingolipids (GSLs), which have resulted in establishment of many new GSLs, particularly the extended globo-series and extended and/or branched lacto-series structures (including A1, A2, B, H, Forssman, and I/i antigens), and their changes associated with ontogenic development and oncogenic transformation. Along this line of studies, I and my colleagues established structures of many tumor-associated antigens expressed in experimental tumors and human cancers, which provide the basis for diagnosis and vaccine development. Some of the tumor-associated GSL antigens are adhesion molecules and promote tumor metastasis. As an initial step in providing a genetic basis of glycosylation, we cloned genes for blood group A and B transferases and elucidated the structures of ABO alleles. We found that GSLs, particularly gangliosides, are modulators of signal transduction through interaction with tyrosine kinases, and identified GSLs themselves as adhesion molecules when clustered in GSL microdomains organized with signal transducer molecules. Thus, cell adhesion based on GSL-to-GSL or GSL-to-ligand interaction at the microdomain causes activation of Src family kinases and small G-proteins, and simultaneously modulates cellular phenotype.