The role of glycosylation in receptor activation

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Mammalian receptor tyrosine kinases (RTKs) are the high affinity cell surface receptors for many growth factors, cytokines and hormones. Approximately 20 different RTK classes have been identified. Most RTKs are single, glycosylated subunit receptors but some for example, the insulin receptor exist as multimeric complexes. When a growth factor binds to the extracellular domain of an RTK, its dimerization is triggered with other adjacent RTKs. Dimerization leads to a rapid activation of the receptor's cytoplasmic kinase domains. The activated receptor then becomes autophosphorylated on multiple specific intracellular tyrosine residues. Although the signaling pathways of RTKs are well characterized, the parameters controlling dimerization and the interactions between the receptors and their ligands still remain poorly defined. For nerve growth factor (NGF) TrkA receptors, glycosylation is required to localize the receptor to the cell surface where glycosylation was suggested to prevent receptor autophosphorylation Indeed, glycosylation of cell membrane bound RTKs may be an important requirement for their transport and function. For an example, partial glycosylation is an important requirement for at least the processing and/or hormone-binding activity of RTK insulin receptor, and epidermal-growth-factor receptor. To date, the precise role of RTK glycosylation in receptor activation is unknown. Here, we discover a direct link between Trk glycosylation and receptor activation following natural ligand interaction (Woronowicz et al., Glycobiology 17:10-24, 2007). Our recent preliminary data indicate that ligand binding to Trk as well as epidermal growth factor receptors (EGFR) and insulin receptors induces lysosomal Neu1 sialidase activity which influences the receptor desialylation and, consequently, the induction of RTK activation. These observations suggest for the first time that RTK activation is regulated by lysosomal Neu1 sialidase induction, and thus we identify a critical parameter involved with ligand binding to RTKs, which has not been previously observed. Neu1 sialidase may be a common master enzyme regulating the process of dimerization and activation of RTK receptors.