Role of glycosyltransferases in carcinogenesis; growth factor signaling and EMT/MET programs

Abstract

The glycosylation of cell surface receptors has been shown to regulate each step of signal transduction, including receptor trafficking to the cell surface, ligand binding, dimerization, phosphorylation, and endocytosis. In this review we focus on the role of glycosyltransferases that are involved in the modification of N-glycans, such as the effect of branching and elongation in signaling by various cell surface receptors. In addition, the role of those enzymes in the EMT/MET programs, as related to differentiation and cancer development, progress and therapy resistance is discussed.

Keywords: Cell surface receptor; Collectin; EGFR; EMT programs; ErbB receptors; Fut8; GM3; GnT-III; GnT-V; ST6Gal1.

Fig. 1

N-glycosylation sites of ErbB receptors. The upper panel indicates the schematic diagram showing the structural protein domain and N-glycosylation sites of ErbB receptors. The amino acid numbering is for the mature form of the receptors and does not include signal peptides of the N-terminal 24 amino acids of EGFR, the 22 amino acids of ErbB2, the 19 amino acids of ErbB3, or the 25 amino acids of ErbB4. The lower panel indicates the alignment of glycosylation sites of ErbB receptors

Fig. 2

Site specific N-glycosylation status of EGFR. For each category (endogenous EGFR in A431, recombinant EGFR expressed in CL1-5, and recombinant sEGFR expressed in CHO-K1), the left column indicates glycosylation occupancy and the right column indicates the type of N-glycan. In the glycosylation occupancy columns, ◯ indicates 100% glycosylation and × indicates no glycosylation. ^aData from Zhen et al. [15]. The data of glycosylation status are common to full length EGFR and 105 kDa sEGFR, but the data of the N-glycan structure are of 105 kDa sEGFR. ^bData from Liu et al. [16]. 100% glycosylation and partial glycosylation are not discriminated here. ^cData from Hasegawa et al. [17]

Fig. 3

Site specific N-glycosylation status of ErbB3. In the glycosylation occupancy columns, ◯ indicates 100% glycosylation and × indicates no glycosylation. ^aData from Takahashi et al. (under submission)

Fig. 4

EMT/MET programs and changes in glycosyltransferases. Various effects of GnT-V, Fut8, ST6Gal1 and GnT-III in EMT/MET programs. GnT-III is implicated in the MET whereas ST6Gal1, GnT-V and Fut8 are implicated in EMT and it is possible that these changes are stimulated by various factors such as signaling molecules related to oxidative stress, via various signaling molecules including transcription factors such as ZEB1, 2, which are implicated in both EMT and MET