Disease relevance of MAL

• Caveolin-1 and MAL are located on prostasomes secreted by the prostate cancer PC-3 cell line [1].
• MAL2, a novel raft protein of the MAL family, is an essential component of the machinery for transcytosis in hepatoma HepG2 cells [2].
• In polarized epithelial Madin-Darby canine kidney cells, MAL is necessary for normal apical transport and accurate sorting of the influenza virus hemagglutinin [3].
• Among 41 Hodgkin lymphomas, 3 nodular-sclerosing cases with mediastinal involvement showed MAL-positive Reed Sternberg cells [4].
• Among B-cell lymphomas (n = 110), MAL expression in tumor cells was observed in 21/33 primary mediastinal large B-cell lymphomas (70%) and in 3/5 plasmacytoma/myeloma, but not in all other B-cell lymphomas with the exception of 1/33 nonmediastinal diffuse large B-cell lymphomas [4].

High impact information on MAL

• Herein, we present the functional characterization of MAL2, a member of the MAL protein family, in polarized HepG2 cells [2].
• cDNA cloning and sequence of MAL, a hydrophobic protein associated with human T-cell differentiation [5].
• The predicted configuration of the MAL protein resembles the structure of integral proteins that form pores or channels in the plasma membrane and that are believed to act as transporters of water-soluble molecules and ions across the lipid bilayer [5].
• The cDNA encodes a highly hydrophobic protein, termed MAL, that lacks a hydrophobic leader peptide sequence and contains four potential transmembrane domains separated by short hydrophilic segments [5].
• Prior to myelin formation MAL is also found in immature Schwann cells [6].

Biological context of MAL

• RNase protection analysis revealed that the previously described MAL mRNA, which contains the sequences present in the four exons, is the mRNA species predominant in T-cells [7].
• Together, these observations suggest that, as predicted for integral membrane members of the late protein transport machinery, MAL is an itinerant protein cycling between the TGN and the plasma membrane [3].
• This subcellular localization is in agreement with the presence of a RWKSS motif in the COOH-terminal tail of MAL, next to its last putative transmembrane domain, that fits with one of the consensus sequences (RXKXX) for residency in the endoplasmic reticulum for transmembrane proteins [7].
• The ectopic expression of these modified MAL proteins allowed us to investigate the surface expression of MAL and its movement through different compartments after internalization with the use of a combination of assays, including surface biotinylation, surface binding of anti-FLAG antibodies, neuraminidase sensitivity, and drug treatments [3].
• Protease activation in apoptosis induced by MAL [8].

Anatomical context of MAL

• We have addressed the study of the glycolipid-enriched membranes in cells expressing endogenously only either MAL (Jurkat T cells) or caveolin (epithelial A498 cells) and in polarized MDCK cells which express both proteins simultaneously [9].
• Caveolin and MAL, two protein components of internal detergent-insoluble membranes, are in distinct lipid microenvironments in MDCK cells [9].
• The MAL proteolipid and caveolin have been identified as components of internal detergent-insoluble membrane microdomains enriched in glycolipids and cholesterol [9].
• MAL, a proteolipid in glycosphingolipid enriched domains: functional implications in myelin and beyond [6].
• The role of MAL in the formation, stabilisation and maintenance of glycosphingolipid-enriched membrane microdomains and its contribution to specific membrane properties in myelin and epithelial cells are discussed [6].

Associations of MAL with chemical compounds

• When TX100 extracts from Jurkat cells were subjected to centrifugation to equilibrium in sucrose gradients we found MAL exclusively in the floating fractions, together with molecules characteristic of the T-cell insoluble complexes, such as the tyrosine kinase p56lck, the glycosylphosphatidylinositol-anchored protein CD59 and the ganglioside GM1 [10].

Other interactions of MAL

• Our results suggest that MAL family proteins are associated with caveolin-1 in a multivesicular compartment that may be involved in prostasomal secretion in PC-3 cells [1].
• BENE, a novel raft-associated protein of the MAL proteolipid family, interacts with caveolin-1 in human endothelial-like ECV304 cells [11].
• Since an antagonistic anti-CD95 receptor antibody, ZB4, did not influence the MAL-induced killing, we conclude that this process does not involve the CD95-mediated pathway [8].
• Amplification by the polymerase chain reaction of cDNA from different T-cell samples indicated the existence of four different forms of MAL mRNA, termed MAL-a, -b, -c, and -d, that arise from differential usage of exons II and/or III [12].

Analytical, diagnostic and therapeutic context of MAL

• Immunofluorescence analysis in MDCK cells indicated that both MAL and caveolin were located in the Golgi region, whereas caveolin was found in addition at the cell surface [9].
• We have characterized the embryonic and postnatal expression of MAL in the rat nervous system by in situ hybridization, immunocytochemistry, and western blotting and compared it with that of other myelin constituents [13].
• Moreover, immuno-electron microscopy revealed that MAL, besides its localization in compact myelin, is also localized to Schmidt-Lanterman incisures [14].
• Sequence analysis of the T-cell-specific MAL gene revealed four exons, each encoding a hydrophobic, presumably membrane-associated, segment and its adjacent hydrophilic sequence [12].

References