Polysialic acid (polySia) is a novel glycan that posttranslationally modifies neural cell adhesion
molecules (NCAMs) in mammalian cells. Up-regulation of polySia-NCAM expression or NCAM
polysialylation is associated with tumor cell migration and progression in many metastatic cancers and
neurocognition. It has been known that two highly homologous mammalian polysialyltransferases
(polySTs), ST8Sia II (STX) and ST8Sia IV (PST), can catalyze polysialylation of NCAM, and two
polybasic domains, polybasic region (PBR) and polysialyltransferase domain (PSTD) in polySTs play
key roles in affecting polyST activity or NCAM polysialylation. However, the molecular mechanisms of
NCAM polysialylation and cell migration are still not entirely clear. In this minireview, the recent research
results about the intermolecular interactions between the PBR and NCAM, the PSTD and
cytidine monophosphate-sialic acid (CMP-Sia), the PSTD and polySia, and as well as the intramolecular
interaction between the PBR and the PSTD within the polyST, are summarized. Based on these cooperative
interactions, we have built a novel model of NCAM polysialylation and cell migration mechanisms,
which may be helpful to design and develop new polysialyltransferase inhibitors.