The metastasis suppressor gene KAI1 (Kangai1), located on chromosome 11p11.2, was originally identified in a screen for genes on chromosome 11 that suppressed metastasis of rat AT6.1 prostate cancer cells. Re-expression of KAI1 in AT6.1 reduced the formation of metastases without affecting primary tumor growth [1
]. KAI1 was previously described as CD82, a lymphocyte cell surface protein involved in activation of T cell receptor [2
]. CD82 is also known as antigens R2, C33, IA4 and 4F9 [3
]. Subsequent studies confirmed the metastasis suppressor function of CD82 in hepatocarcinoma, melanoma, sarcoma, pancreatic and breast cancer cell lines [7
]. The importance of CD82 in cancer progression is underscored by the observation that downregulation of CD82 mRNA and protein is associated with advanced stages of many malignancies (reviewed in [12
]) including prostate, colon, lung, pancreatic, breast, ovarian and other cancers.
CD82 is a member of the tetraspanin superfamily of glycoproteins. Tetraspanins are characterized by four transmembrane domains with conserved polar residues, which may help to stabilize a tight tertiary structure [13
] (). They have short intracellular N- and C-termini, one short (ECL1) and one long (ECL2) extracellular hydrophilic loops and a very short intracellular loop. The intracellular juxtamembrane cysteines are usually modified by palmitoylation, which contributes to the formation of a tetraspanin web with other tetraspanins as well as non-tetraspanin proteins. Based on a modeled structure of CD81, a related tetraspanin, the N terminus likely forms a membrane-parallel amphipathic helix when palmitoylated whereas the C terminus likely adopts a random structure [13
]. The short ECL1 appears to possess a β-strand that is enriched with hydrophobic residues and may interact with the hydrophobic groove of ECL2 [13
]. ECL2 is the most variable region among the tetraspanins and provide antigenic specificity as most monoclonal antibodies map to this region. ECL2 also contains the signature Cys-Cys-Gly motif, which forms two disulfide bonds with two other conserved cysteines in ECL2. ECL2 can be divided into a constant region and a variable region: The constant region may contribute to oligomerization with other tetraspanins while the variable region may contribute to interactions with other non-tetraspanin proteins [13
]. ECL2 of CD82 contains 3 consensus N-linked glycosylation sites. When overexpressed, CD82 sometimes show a wide range of molecular weights on SDS-PAGE (40–90 kDa) due to varying degrees of glycosylation. Glycosylation of tetraspanins is important not only for their transit through the endoplasmic reticulum (ER) during maturation but also for complex formation and cellular functions [15
Tetraspanins form large multimeric complexes that consist of tetraspanins as well as other membrane and cytosolic proteins such as receptor tyrosine kinases, integrins, and adaptor proteins that are integral to signaling cascades. They are also enriched for specific lipids including gangliosides. These complexes are clustered in specialized membrane domains known as "tetraspanins-enriched microdomains" (TEM). CD82 does not have any evident enzymatic activity. As discussed in the following sections, CD82 seems to instead function by modulating the levels, trafficking or activity of its interacting partners in the TEM.