Tetraspanins are also proposed to link integrins to cytoplasmic signaling molecules, thereby diversifying integrin function (7,38)

Tetraspanins are also proposed to link integrins to cytoplasmic signaling molecules, thereby diversifying integrin function (7,38). normal inTssc6gt/gtmice. WhereasTssc6gt/gtB cells responded normally to lipopolysaccharide, anti-CD40, and anti-immunoglobulin M stimulation,Tssc6gt/gtT cells showed enhanced responses to concanavalin A, anti-CD3, and anti-CD28. This increased proliferation byTssc6-deleted T lymphocytes was due to increased interleukin 2 production following T-cell receptor stimulation. These results demonstrate thatTssc6is not required for normal development of the hematopoietic system but may play a TRx0237 (LMTX) mesylate role Rabbit Polyclonal to NOM1 in the negative regulation of peripheral T-lymphocyte proliferation. The tetraspanins (transmembrane 4 superfamily) are a large family of integral membrane proteins conserved through evolution (39). Tetraspanin proteins contain four highly conserved hydrophobic transmembrane domains. There are two extracellular loops of unequal size and short, intracytoplasmic amino and carboxy termini. The small extracellular loop lies between transmembrane domains 1 and 2, and the large extracellular loop, which confers much of the functional specificity, lies between transmembrane domains 3 and 4. In contrast to the transmembrane domains, the extracellular domains of the family show considerable divergence. There are, however, three motifsCCG, PXSC, and EGCcontaining four highly conserved cysteine residues in the major extracellular domain. The tetraspanins are conceptualized to form a multiprotein network, or web, in the cell membrane, interacting with tetraspanin family TRx0237 (LMTX) mesylate members, other integral membrane proteins, and intracytoplasmic signaling molecules (7,17,39). Functional predictions derived from a structural analysis of the large extracellular loop suggest that two low-polarity regions in the loop may provide the binding sites for multiple protein partners (8). Tetraspanin associations were TRx0237 (LMTX) mesylate initially investigated by immunoprecipitating complexes in cell membrane lysates treated with mild detergents. Such complexes were invariably large and contained multiple proteins, including other tetraspanins. More recently, associations within the tetraspanin network have been dissected according to the ability of tetraspanin-containing complexes to withstand disruption by detergents of graded hydrophobicity (3). Tetraspanin complexes held to be direct TRx0237 (LMTX) mesylate and highly specific include those between integrins 31 and 61 and tetraspanin CD151, 41 and CD81 (3), and CD9 and CD81 and the novel immunoglobulin superfamily proteins EWI-2 and EWI-F (the prostaglandin F2 alpha receptor regulatory protein) (3,31). Tetraspanins have functional roles in cell motility, membrane fusion, proliferation, and adaptive immunity (7,14,17,39). In some cases, nontetraspanin molecules incorporated into the tetraspanin web may be responsible for the functional effect; the direct role, if any, of the tetraspanin is not yet clear. Many adhesion molecules and, in particular, the 1 integrins, form molecular associations with tetraspanin molecules (3,7). It is this partnership that likely underpins the role of tetraspanins in cell motility and cancer metastasis (38). Tetraspanins are also proposed to link integrins to cytoplasmic signaling molecules, thereby diversifying integrin function (7,38). An essential role for CD9 in sperm-egg fusion was revealed by the infertility of CD9 knockout mice. CD9 is also suggested to participate in megakaryocyte membrane fusion (4) and (with CD81) in myotubule formation (33). Tetraspanin associations have been observed with many lymphocyte cell surface proteins, usually under mild detergent conditions. Coimmunoprecipitating molecules include CD2, CD4 and CD8, and major histocompatibility complex class II (MHC-II). The tetraspanin CD81 is a member of the B-cell receptor complex comprising CD19, CD21, and Leu13. In this context, tetraspanins have been implicated in the control of lymphocyte activation and proliferation (14,15,17). Studies on CD81 and CD37 knockout mice have revealed a role for tetraspanins in the immune response. CD81-null B lymphocytes have variably altered proliferation when stimulated in vitro, while T lymphocytes are hyperproliferative to a range of mitogens (20). When immunized with a T-cell-dependent antigen, CD81-null mice were unable to mount an effective immune response (15,16,20). CD81 was determined to be important for effective B- and T-cell interaction and interleukin 4 (IL-4) production by T cells (15). Deletion of CD37 also had a negative effect on B-cell-T-cell collaboration and B-cell function in response to immunization with T-cell-independent antigens (9). Several groups, using different approaches, have TRx0237 (LMTX) mesylate identified the humanTSSC6gene, also known asPHEMX. The locus was present on a fragment of 11p15 chromosome that suppressed the growth of a rhabdomyosarcoma cell line (hence, tumor-suppressing subchromosomal transferable fragment cDNA 6) (22). The murineTssc6gene was mapped to a syntenic region of distal chromosome 7 within a 1-Mb imprinted domain, althoughTssc6itself was not imprinted (22).Tssc6, designatedPhemx, was.