Role of Glycans on Key Cell Surface Receptors That Regulate Cell Proliferation and Cell Death

Abstract

Cells undergo proliferation and apoptosis, migration and differentiation via a number of cell surface receptors, most of which are heavily glycosylated. This review discusses receptor glycosylation and the known roles of glycans on the functions of receptors expressed in diverse cell types. We included growth factor receptors that have an intracellular tyrosine kinase domain, growth factor receptors that have a serine/threonine kinase domain, and cell-death-inducing receptors. N- and O-glycans have a wide range of functions including roles in receptor conformation, ligand binding, oligomerization, and activation of signaling cascades. A better understanding of these functions will enable control of cell survival and cell death in diseases such as cancer and in immune responses.

Keywords: N-glycans; O-glycans; TGFR; receptors; signaling; tyrosine kinase.

Figure 1

Glycans commonly found on cell surface receptors. The extracellular domains of receptors are glycosylated, and specific glycans have been shown to either block or activate receptor dimerization or activation. Virtually all receptors have multiple N-glycans that include oligomannose, complex or bisected structures. Fucose bound to the N-glycan core or to N-acetyllactosamine chains and sialic acid are among the terminal sugar residues. Some receptors have O-glycans that are commonly comprised of simple GalNAc (Tn antigen), core 1 (T antigen) and sialyl-T antigen structures. Not all possible glycosylation sites are occupied and the role of these glycans may vary between occupied sites, cell types and the specific receptors.

Figure 2

Tyrosine kinase receptors. Growth factor receptors have an extracellular domain that binds a growth factor and a cytoplasmic Tyrosine kinase domain (oncoprotein) that is essential for the signaling through a number of pathways that promote cell proliferation. Many of these receptors are of critical importance in tumor growth. Ligand binding induces receptor dimerization and activation of the Tyrosine kinases, phosphorylation of the cytoplasmic domain and induction of signaling pathways. (A) Only one of the N-glycans on each of the epidermal growth factor receptor (EGFR) subunits is shown. Fibroblast growth factor receptor (FGFR) also has multiple N-glycans and can carry O-glycans and have glycosaminoglycan coreceptors (heparin, HS). Vascular endothelial growth factor receptor (VEGFR) has core 1 O-glycans and is highly N-glycosylated. (B) The insulin binding growth factor receptor (INSR) and insulin-like growth factor receptor (IGFR) are N-glycosylated glycoproteins. MET receptor binds hepatocyte growth factor (HGF) glycoprotein and is both N- and O-glycosylated. (C) Tyrosine kinase growth factor receptors expressed on neurons include TrkA, TrkB, TrkC and RET involved in cell proliferation, neurite outgrowth and other functions. TrkA has multiple N-glycans and interacts with its nerve growth factor (NGF) ligand, as well as ganglioside GM1 and neuraminidase Neu1 on the cell membrane. The RET dimer requires coreceptors that are glycosylphosphatidylinositol (GPI)-anchored at the membrane and bind glial cell-derived neurotrophic factor (GDNF).

Figure 3

TGF-β receptors are serine/threonine kinases. Transforming growth factor receptors (TGFR) are heterodimeric transmembrane receptors that form tetrameric transmembrane receptors. Binding to TGF-β initiates intracellular serine/threonine phosphorylation, cell proliferation, differentiation and many other biological responses. The signaling cascades and gene regulation involve SMAD phosphorylation. TGFR has several functionally important N-glycans, and may carry glycosaminoglycans and O-glycans. A Fuc residue at the N-glycan core plays a major role in receptor function. Truncated, GPI-anchored, receptor analogs regulate the binding of TGF-β.

Figure 4

Death receptors initiate apoptosis pathways. Fas and TNFα-related apoptosis-inducing ligand (TRAIL) receptors bind to a trimeric ligand (FasL or TRAIL) and form trimeric receptors that initiate caspase cleavages and apoptosis signaling pathways through Fas-associated protein with death domain (FADD) and death-inducing signaling complex (DISC). Fas has two N-glycans while DR4 has only one N-glycan and DR5 has no N-glycans. Both DR4 and DR5 have O-glycans. O-GlcNAc residues may be present on the cytoplasmic domain. TRAIL receptors are also controlled by their N-glycans. The presence of unmodified GalNAc residues (Tn antigen) leads to attenuation of receptor functions.