Lipid Raft-Mediated Regulation of Hyaluronan-CD44 Interactions in Inflammation and Cancer

Abstract

Hyaluronan is a major component of the extracellular matrix and plays pivotal roles in inflammation and cancer. Hyaluronan oligomers are frequently found in these pathological conditions, in which they exert their effects via association with the transmembrane receptor CD44. Lipid rafts are cholesterol- and glycosphingolipid-enriched membrane microdomains that may regulate membrane receptors while serving as platforms for transmembrane signaling at the cell surface. This article focuses on the recent discovery that lipid rafts regulate the interaction between CD44 and hyaluronan, which depends largely on hyaluronan's size. Lipid rafts regulate CD44's ability to bind hyaluronan in T cells, control the rolling adhesion of lymphocytes on vascular endothelial cells, and regulate hyaluronan- and CD44-mediated cancer cell migration. The implications of these findings for preventing inflammatory disorders and cancer are also discussed.

Keywords: a disintegrin and metalloproteinase; cholesterol; ectodomain shedding; extracellular matrix remodeling; membrane dynamics; membrane raft; oligosaccharides; transmembrane signaling.

Figure 1

The structure and size of hyaluronan, and its interaction with CD44 in the lipid raft. (A) Chemical structure of hyaluronan. Hyaluronan is a linear glycosaminoglycan consisting of repeating disaccharide units of d-glucuronic acid (GlcUA) and N-acetyl-glucosamine (GlcNAc) with the structure [β1,4-GlcUA-β-1,3-GlcNAc-]n. (B) Hyaluronan size and its relevance to inflammation and cancer. The sizes of hyaluronan are categorized according to Weigel’s nomenclature (5), and shown in the log scale of the molecular weight: oligomeric hyaluronan (oHA; 1 × 10³–1 × 10⁴), small hyaluronan (sHA; 1 × 10⁴–1 × 10⁵), intermediate hyaluronan (iHA; 1 × 10⁵–1 × 10⁶), and large hyaluronan (_LHA; 1 × 10⁶–1 × 10⁷). Hyaluronan’s molecular weight in normal physiological conditions ranges from 1 × 10⁵ to 1 × 10⁷, whereas the low-molecular weight hyaluronan has relevance to inflammation and cancer. The very high-molecular weight hyaluronan from naked mole rat (molecular weight, 6 × 10⁶–1.2 × 10⁷) has an anti-malignant activity (6). (C) CD44 structure. CD44 consists of four regions; hyaluronan-binding domain (HABD), stalk domain, transmembrane region, and cytoplasmic tail.