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Gene Review

MAL2  -  mal, T-cell differentiation protein 2...

Homo sapiens

Synonyms: Protein MAL2
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Disease relevance of MAL2

  • MAL2, a novel raft protein of the MAL family, is an essential component of the machinery for transcytosis in hepatoma HepG2 cells [1].
  • Alterations in MAL2 expression, distribution, and appearance were found in specific types of follicular cell-derived carcinomas [2].
  • Detection of MAL2 significantly increased after infection and it was colocalized with HSV-1 proteins [3].
  • Given that MALP-2 has been recently shown to be expressed at the surface of M. fermentans as a molecular entity, sMALP-2 constitutes a valuable surrogate for investigating immunomodulation by these microorganisms and evaluating the role that this activity plays in the development of inflammatory diseases associated with mycoplasma infections [4].
  • Anti-inflammatory drugs inhibited MALP-2-mediated bone resorption by about 30% [5].

High impact information on MAL2

  • Herein, we present the functional characterization of MAL2, a member of the MAL protein family, in polarized HepG2 cells [1].
  • MAL2 greatly colocalized in subapical endosome structures with transcytosing molecules en route to the apical surface [1].
  • MAL2 depletion did not affect the internalization of these molecules but produced their accumulation in perinuclear endosome elements that were accessible to transferrin [1].
  • MAL2 resided selectively in rafts and is predominantly distributed in a compartment localized beneath the subapical F-actin cytoskeleton [1].
  • Most surprisingly, we have found that an R stereoisomer of diacylated macrophage-activating lipopeptide 2 (MALP-2) exclusively activates epithelial cells through TLR6 and -2 but not through TLR1 and -2 [6].

Chemical compound and disease context of MAL2


Biological context of MAL2

  • The gene MAL2, which was localized to human chromosomal band 8q23 and shown to consist of four exons, is predominantly expressed in human kidney, lung, and liver [8].
  • In addition, the specific alterations in MAL and/or MAL2 expression observed in specific types of carcinoma provides a basis to understand the loss of the polarized phenotype that frequently accompanies the neoplastic transformation process [9].
  • A significant reduction in TNFalpha-induced apoptosis was demonstrated by stimulation of U937 cells with M. fermentans total proteins, LPMf or MALP-2 (M. fermentans synthetic lipopeptide), but not with M. fermentans hydrophilic protein preparation (AqMf) [10].
  • Mycoplasma fermentans lipoproteins and a synthetic lipopeptide, MALP-2, showed cytocidal activity towards HEK293 cells transfected with a TLR2-encoding plasmid [11].
  • A gene array experiment suggested that MALP-2 stimulates the release of various mediators involved in wound healing [12].

Anatomical context of MAL2

  • MAL2 is predicted to be 176 residues (19 kDa) with four transmembrane domains and is 35.8% identical to MAL, a proteolipid required in apical vesicle transport [8].
  • Expression and distribution of MAL2, an essential element of the machinery for basolateral-to-apical transcytosis, in human thyroid epithelial cells [2].
  • Herein, we have investigated the expression and distribution of MAL2 in the human thyroid [2].
  • Biochemical analysis in primary thyrocyte cultures indicated that MAL2 exclusively resides in raft membranes [2].
  • Many different types of specialized secretory cells, either organized in discrete clusters (e.g., endocrine cells in the pancreas) or in endocrine glands (e.g., prostate), were also positive for MAL2 [13].

Associations of MAL2 with chemical compounds


Regulatory relationships of MAL2

  • The remaining ALS2 allele was placed under control of the C. albicans MAL2 promoter to create an als2Delta/PMAL2-ALS2 strain (named 2342) [18].
  • MALP-2 stimulated the liberation of IL-6, while no tumor necrosis factor was detectable [5].

Other interactions of MAL2

  • Identification of MAL2, a novel member of the mal proteolipid family, though interactions with TPD52-like proteins in the yeast two-hybrid system [8].
  • To understand how transcytosis can be apparently mediated at a distance, we have analyzed the dynamics of machinery and cargo by live-cell imaging of MAL2 and transcytosing CD59, a GPI-anchored protein, in HepG2 cells [19].
  • We also identified other novel genes, such as insulin-like growth factor binding protein 5 and a cDNA clone similar to proteolipid MAL2 [20].
  • Here we show that TLR6-deficient (TLR6(-/-)) cells are unresponsive to MALP-2 but retain their normal responses to lipopeptides of other bacterial origins [14].
  • The effects of inhibitors of NF-kappaB, MEK1/2 and p38 on MALP-2-induced PGE(2) production were also evaluated [7].

Analytical, diagnostic and therapeutic context of MAL2


  1. MAL2, a novel raft protein of the MAL family, is an essential component of the machinery for transcytosis in hepatoma HepG2 cells. de Marco, M.C., Martín-Belmonte, F., Kremer, L., Albar, J.P., Correas, I., Vaerman, J.P., Marazuela, M., Byrne, J.A., Alonso, M.A. J. Cell Biol. (2002) [Pubmed]
  2. Expression and distribution of MAL2, an essential element of the machinery for basolateral-to-apical transcytosis, in human thyroid epithelial cells. Marazuela, M., Martín-Belmonte, F., García-López, M.A., Aranda, J.F., de Marco, M.C., Alonso, M.A. Endocrinology (2004) [Pubmed]
  3. High susceptibility of a human oligodendroglial cell line to herpes simplex type 1 infection. Bello-Morales, R., Fedetz, M., Alcina, A., Tabarés, E., López-Guerrero, J.A. J. Neurovirol. (2005) [Pubmed]
  4. A Mycoplasma fermentans-derived synthetic lipopeptide induces AP-1 and NF-kappaB activity and cytokine secretion in macrophages via the activation of mitogen-activated protein kinase pathways. Garcia, J., Lemercier, B., Roman-Roman, S., Rawadi, G. J. Biol. Chem. (1998) [Pubmed]
  5. Effect of MALP-2, a lipopeptide from Mycoplasma fermentans, on bone resorption in vitro. Piec, G., Mirkovitch, J., Palacio, S., Mühlradt, P.F., Felix, R. Infect. Immun. (1999) [Pubmed]
  6. Domain exchange between human toll-like receptors 1 and 6 reveals a region required for lipopeptide discrimination. Omueti, K.O., Beyer, J.M., Johnson, C.M., Lyle, E.A., Tapping, R.I. J. Biol. Chem. (2005) [Pubmed]
  7. Macrophage-activating lipopeptide-2 induces cyclooxygenase-2 and prostaglandin E(2) via toll-like receptor 2 in human placental trophoblast cells. Mitsunari, M., Yoshida, S., Shoji, T., Tsukihara, S., Iwabe, T., Harada, T., Terakawa, N. J. Reprod. Immunol. (2006) [Pubmed]
  8. Identification of MAL2, a novel member of the mal proteolipid family, though interactions with TPD52-like proteins in the yeast two-hybrid system. Wilson, S.H., Bailey, A.M., Nourse, C.R., Mattei, M.G., Byrne, J.A. Genomics (2001) [Pubmed]
  9. Expression of MAL and MAL2, two elements of the protein machinery for raft-mediated transport, in normal and neoplastic human tissue. Marazuela, M., Alonso, M.A. Histol. Histopathol. (2004) [Pubmed]
  10. The inhibitory effect of Mycoplasma fermentans on tumour necrosis factor (TNF)-alpha-induced apoptosis resides in the membrane lipoproteins. Gerlic, M., Horowitz, J., Farkash, S., Horowitz, S. Cell. Microbiol. (2007) [Pubmed]
  11. Stimulation of human Toll-like receptor (TLR) 2 and TLR6 with membrane lipoproteins of Mycoplasma fermentans induces apoptotic cell death after NF-kappa B activation. Into, T., Kiura, K., Yasuda, M., Kataoka, H., Inoue, N., Hasebe, A., Takeda, K., Akira, S., Shibata, K. Cell. Microbiol. (2004) [Pubmed]
  12. The macrophage-activating lipopeptide-2 accelerates wound healing in diabetic mice. Deiters, U., Barsig, J., Tawil, B., Mühlradt, P.F. Exp. Dermatol. (2004) [Pubmed]
  13. Expression of MAL2, an integral protein component of the machinery for basolateral-to-apical transcytosis, in human epithelia. Marazuela, M., Acevedo, A., García-López, M.A., Adrados, M., de Marco, M.C., Alonso, M.A. J. Histochem. Cytochem. (2004) [Pubmed]
  14. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Takeuchi, O., Kawai, T., Mühlradt, P.F., Morr, M., Radolf, J.D., Zychlinsky, A., Takeda, K., Akira, S. Int. Immunol. (2001) [Pubmed]
  15. Stimulation of mast cells via FcvarepsilonR1 and TLR2: The type of ligand determines the outcome. Fehrenbach, K., Port, F., Grochowy, G., Kalis, C., Bessler, W., Galanos, C., Krystal, G., Freudenberg, M., Huber, M. Mol. Immunol. (2007) [Pubmed]
  16. Synthetic mycoplasma-derived lipopeptide MALP-2 induces maturation and function of dendritic cells. Weigt, H., Mühlradt, P.F., Emmendörffer, A., Krug, N., Braun, A. Immunobiology (2003) [Pubmed]
  17. CD36 is a sensor of diacylglycerides. Hoebe, K., Georgel, P., Rutschmann, S., Du, X., Mudd, S., Crozat, K., Sovath, S., Shamel, L., Hartung, T., Zähringer, U., Beutler, B. Nature (2005) [Pubmed]
  18. Analysis of the Candida albicans Als2p and Als4p adhesins suggests the potential for compensatory function within the Als family. Zhao, X., Oh, S.H., Yeater, K.M., Hoyer, L.L. Microbiology (Reading, Engl.) (2005) [Pubmed]
  19. Dynamics of MAL2 during glycosylphosphatidylinositol-anchored protein transcytotic transport to the apical surface of hepatoma HepG2 cells. de Marco, M.C., Puertollano, R., Martínez-Menárguez, J.A., Alonso, M.A. Traffic (2006) [Pubmed]
  20. Gene expression profiling identifies matriptase overexpression in malignant mesothelioma. Hoang, C.D., D'Cunha, J., Kratzke, M.G., Casmey, C.E., Frizelle, S.P., Maddaus, M.A., Kratzke, R.A. Chest (2004) [Pubmed]
  21. Toll-like receptor 2- and 6-mediated stimulation by macrophage-activating lipopeptide 2 induces lipopolysaccharide (LPS) cross tolerance in mice, which results in protection from tumor necrosis factor alpha but in only partial protection from lethal LPS doses. Deiters, U., Gumenscheimer, M., Galanos, C., Mühlradt, P.F. Infect. Immun. (2003) [Pubmed]
  22. The HIV-1 matrix protein p17 can be efficiently delivered by intranasal route in mice using the TLR 2/6 agonist MALP-2 as mucosal adjuvant. Becker, P.D., Fiorentini, S., Link, C., Tosti, G., Ebensen, T., Caruso, A., Guzmán, C.A. Vaccine (2006) [Pubmed]
  23. Direct stimulatory effects of the TLR2/6 ligand bacterial lipopeptide MALP-2 on neutrophil granulocytes. Wilde, I., Lotz, S., Engelmann, D., Starke, A., van Zandbergen, G., Solbach, W., Laskay, T. Med. Microbiol. Immunol. (2007) [Pubmed]
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