Dissecting the diverse functions of the metastasis suppressor CD82/KAI1

Abstract

The recent identification of metastasis suppressor genes, the products of which inhibit metastasis but not primary tumor growth, distinguishes oncogenic transformation and tumor suppression from a hallmark of malignancy, the ability of cancer cells to invade sites distant from the primary tumor. The metastasis suppressor CD82/KAI1 is a member of the tetraspanin superfamily of glycoproteins. CD82 suppresses metastasis by multiple mechanisms including inhibition of cell motility and invasion, promotion of cell polarity as well as induction of senescence and apoptosis in response to extracellular stimuli. A common feature of these diverse effects is CD82 regulation of membrane organization as well as protein trafficking and interactions, which affects cellular signaling and intercellular communication.

Figure 1. Schematic of CD82 structure

CD82 has four transmembrane domains with conserved polar residues (light blue), which may be important for structural integrity. The long extracellular loop (ECL2) contains six cysteine residues (yellow) predicted to form 3 disulfide bonds (magenta). The glycine residue in the characteristic Cys-Cys-Gly motif is highlighted in red. ECL2 also contains three asparagine (green) residues that are sites for N-linked glycosylation. Juxtamembrane cysteine residues (yellow) are usually palmitoylated. Palmitoylation of the N-terminal cysteine likely holds the N-terminus parallel to the membrane. The C-terminus contains a sorting motif (orange) important for localization to the endocytic pathway.

Figure 2. Schematic of CD82 regulation and functions

CD82 can be transcriptionally activated by p53, JunB, AP2, NF-κB p50 and HIF-1 (below). CD82 expression by p50 is regulated by the alternative recruitment of Tip60/Pontin or β-catenin/Reptin complex. In normal cells, CD82 transcription is repressed by a NCOR/TAB2/HDAC3 complex (not shown), which is displaced by a Tip60/Pontin co-activator complex for p50 in the presence of cytokines. In cancer cells, Tip60 is downregulated and replaced with a β-catenin/Reptin complex, which represses CD82 transcription. Sumoylation of Reptin is required for its repressor function, which can be inactivated by de-sumoylation. ATF3 can also repress p50 induction of CD82. After translation (above), CD82 protein is regulated by quality control mechanisms in the endoplasmic reticulum. This process, known as ER-associated degradation (ERAD), depends on the ubiquitin ligase gp78. In some cancer cells, cAMP promotes CD82 degradation either by enhancing its internalization or accelerating its degradation from the ER. CD82 inhibits metastasis by multiple mechanisms, including inhibiting cell motility and invasion, promoting apoptosis, inducing tumor cell senescence and enhancing exosomal discharge of β-catenin.