Versican: A Dynamic Regulator of the Extracellular Matrix

Abstract

Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan belonging to the aggrecan/lectican family. In adults, this proteoglycan serves as a structural macromolecule of the extracellular matrix in the brain and large blood vessels. In contrast, versican is transiently expressed at high levels during development and under pathological conditions when the extracellular matrix dramatically changes, including in the inflammation and repair process. There are many reports showing the upregulation of versican in cancer, which correlates with cancer aggressiveness. Versican has four classical splice variants, and all the variants contain G1 and G3 domains at N- and C-termini, respectively. There are two glycosaminoglycan attachment domains CSα and CSβ. The largest V0 variant contains both CSα and CSβ, V1 contains CSβ, V2 contains CSα, and the shortest G3 variant has neither of them. Versican degradation is initiated by cleavage at a site in the CSβ domain by ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases. The N-terminal fragment containing the G1 domain has been reported to exert various biological functions, although its mechanisms of action have not yet been elucidated. In this review, we describe the role of versican in inflammation and cancer and also address the biological function of versikine.

Keywords: extracellular matrix; glycosaminoglycan; hyaluronan; matrikine; microenvironment; proteoglycan.

Figure 1.

Vcan splice variants. Four classical variants V0, V1, V2, and V3 and another variant V4 are depicted. These variants are named differently in the database of NCBI. The N-terminal globular domain G1 consists of A, B, and B’ subdomains. The C-terminal globular domain G3 consists of two EGF-like, a lectin-like, and complement reactive protein (CRP)-like subdomains. There are two chondroitin sulfate binding domains, CSα and CSβ. V0 contains both CSα and CSβ, V1 contains CSβ, V2 contains only CSα, and V3 has neither of the two. V4 has an N-terminal region of CSβ. Abbreviations: ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; NCBI, National Center for Biotechnology Information.

Figure 2.

Schematic diagram of V1 core protein. (A) G1 consists of A subdomain, B and B’ subdomains, CSβ contains an initial cleavage site susceptible to ADAMTS-1,4,5,9,15, and 20, termed versicanases. (B) Scheme of interactions among hyaluronan, Vcan G1, and HAPLN1, in comparison with Acan G1 and HAPLN1. By biochemical analysis, the B-B’ stretch is a minimal segment for HA-binding in Acan and Vcan G1 domains, and HAPLN1. Whereas Acan G1 binds to HAPLN1 at both A subdomains, Vcan G1 binds HAPLN1 at both B-B’ stretches. Although Vcan A subdomain enhances the HA-binding affinity of Vcan G1 with HA, it is not required for the HAPLN1 interaction. C, Amino acid sequence of the initial ADAMTS-cleavage site. V1R mice were generated by CRISPR/Cas9 technology. The mutated sequence of both amino acid and DNA is shown. Abbreviation: HAPLN, hyaluronan and proteoglycan link protein.