| Description | MAL belongs to the MAL family of proteolipids including BENE, MAL2 and Plasmolipin. In mouse, the conserved motif of (Q/Y-G-W-V-M-F/Y-V), which is located at the junction of the first extracellular loop and the second membrane-associated domain serves as a fingerprint for the MAL family, although overall amino acid sequence identities between mouse MAL and the related proteins are between 29-37% (Magyar et al., 1997). This motif is also shared in human MAL family.
Molecular mass of the MAL protein is 16700 Da and assigned into proteolipid group based on the solubility feature in lipophilic solvents. MAL is a non-glycosylated integral membrane protein including four transmembrane domains as hydrophobic segments. Each of four exons encodes a hydrophobic membrane-associated segment and its adjacent hydrophilic sequence in the protein structure (Rancano et al., 1994a). A model is proposed about orientation of MAL protein in the membrane (Alonso et al., 1987).
Another feature of MAL is its transmembrane helices constituting the MARVEL (MAL and related proteins for vesicle trafficking and membrane link) domain. This domain is also found approximately in 20 open reading frames of human genome (Sanchez-Pulido et al., 2002). Furthermore, the domain is also found in the tight-junction-associated proteins including occluding, tricellulin, marvelD3 and in the synaptic-membrane-localized synaptophysin and synaptogyrin. Thus, a common characteristic of proteins containing the MARVEL domain is localization to specialized domains within surface membranes (Magal et al., 2009). |
| Expression | Alonso and Weissman originally identified MAL expression in intermediate and late stages of T-lymphocyte differentiation (Alonso and Weissman, 1987). Furthermore, expression of MAL mRNA is also found to be related with differentiation in urothelial cells, neuronal cells (Liebert et al., 1997; Wakeman et al., 1997) and esophageal epithelium (Mimori et al., 2007). Accordingly, expression is prominent in upper layers, while it is weak or absent in basal layers of esophageal epithelium (Marazuela et al., 2003). These results implied a strong relation between differentiation status and MAL expression.
Although four transcripts identified, MAL-a variant containing the all four exons is found to be the most abundantly expressed in several tissues including peripheral blood lymphocytes and HNSCC tissues (Rancano et al., 1994b; Beder et al., 2009). Maruzela et al. defined a detailed expression status for MAL protein by immunostaining in a wide range of human tissues and expression is found to be mainly localized in epithelial cells, myelinating cells and T-lymphocytes (Marazuela et al., 2003). Detailed results according to this study:
A- MAL negative cells and tissues:
- Fibroblasts, endothelial cells, B lymphocytes, skeletal and smooth muscle, skin (keratinized squamous epithelium and subcutaneous fibro-adipose tissue).
B- MAL positive cells and tissues:
- Gastrointestinal tract: Epithelium in esophagus, stomach, ileum, colon, liver, and pancreas.
- Genitourinary tract: Multiple sites of tract including transitional epithelium of the urothelium.
- Respiratory tract: Ciliated columnar epithelium of bronchi and bronchioles, and type 2 pneumocytes of alveolae.
- Hematopoietic system: Expression is restricted to regions rich in T-cells including cortex of thymus and paracortical lymphocytes of lymph node and tonsil.
- Endocrine system: Thyroid follicular cells, medulla of adrenal gland.
- Nervous system: Axons of peripheral nerves and myelinating Schwann cells in peripheral nervous system, oligodendrocytes of white and gray matter in central nervous system.
- Exocrine glands: breast epithelium (Horne et al., 2009). |
| Localisation | The MAL proteolipid is an integral membrane protein and generally embedded in the plasma membrane of epithelial cells (Magal et al., 2009). Expression is generally more pronounced in supranuclear - apical membrane domain for most of the polarized epithelia including gastrointestinal mucosa and thyroid follicular cells (Marazuela et al., 2003) according with its role in polarized sorting.
The protein has been mainly identified as an internal component of glycolipid-enriched membrane (GEM) domains in T-lymphocytes (Millan et al., 1997), in polarized epithelial MDCK cells (Zacchetti et al., 1995) and in myelin-forming cells (Kim et al., 1995). As intracellular placement, the protein is localized to endoplasmic reticulum of T-lymphocytes (Rancano et al., 1994b). |
| Function | Plasma membrane (PM) of epithelial cells divided into apical membrane domain involved in exchange with the organ lumen, and the basolateral domain maintaining contact with neighboring cells and the underlying extracellular matrix. Localizing numerous PM proteins to apical and basolateral domains by direct or indirect pathways result in cell polarization. In the direct pathway, proteins delivered directly from the trans-golgi network (TGN) to the apical PM by raft-dependent or non-raft carriers. Rafts are clustering of glycospingolipids, sphingomyelin and cholesterol into membrane microdomains and therefore also named as GEM (glycosphingolipid- and cholestrol-enriched membrane) domains. These detergent insoluble membranes defined by resistancy to cold extraction with Triton X-100. Several proteins participate in structure of rafts.
MAL is an integral membrane component of raft domains and recycles between the Golgi complex and the apical membrane in MDCK cells (Puertollano et al., 1999a). Although, exact mechanism of MAL function in raft-dependent apical sorting is unknown, MAL family proteolipids are implicated to be potent regulator of apical transport by involving in the assembly and targeting of apical transport platforms and in the formation and stabilization of raft domains. Consensus sorting motifs in the C-terminus function in regulation of raft transport (Puertollano et al., 1997).
In apical sorting, PM proteins are clustered into either glycolipid raft domains or non-raft carriers. MAL and MAL2 together with FAPP2 take part in constitutive apical transport of Influenza hemagglutinin (HA) (Puertollano et al., 1999b) and GPI-anchored proteins (decay-accelerating F factor, folate receptor, GFP-GPI, 5'-nucleotidase, CEA) by lipid-raft-associated mechanism (Weisz et al., 2009). Based on apical sorting of many proteins, MAL is implied to function in establishment of cell polarity, however, MAL knockout mice did not display a clear defect in neuronal and epithelial cell polarity (Harada, 2010).
Related with the location of MAL in membrane microdomains another role is also suggested in cell signaling (Alonso et al., 2001), although there is yet no clear evidence concerning this function. |
| Homology | MAL protein is shown to be widely conserved (94-97%) across species by sequence alignment. In MAL family of human, MAL displays 39% and 36% amino acid sequence identity with BENE and MAL2, respectively and all proteins have four-transmembrane domain structure. |
| The role of lipid rafts in signalling and membrane trafficking in T lymphocytes. |
| Alonso MA, Millan J. |
| J Cell Sci. 2001 Nov;114(Pt 22):3957-65. (REVIEW) |
| PMID 11739628 |
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| cDNA cloning and sequence of MAL, a hydrophobic protein associated with human T-cell differentiation. |
| Alonso MA, Weissman SM. |
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| T-lymphocyte maturation-associated protein gene as a candidate metastasis suppressor for head and neck squamous cell carcinomas. |
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| Clin Cancer Res. 2005 May 15;11(10):3686-96. |
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| MAL promoter hypermethylation as a novel prognostic marker in gastric cancer. |
| Buffart TE, Overmeer RM, Steenbergen RD, Tijssen M, van Grieken NC, Snijders PJ, Grabsch HI, van de Velde CJ, Carvalho B, Meijer GA. |
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| Molecular mechanism of polarized transport. |
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| J Biochem. 2010 May;147(5):619-24. Epub 2010 Mar 30. |
| PMID 20356823 |
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| Down-regulation of members of glycolipid-enriched membrane raft gene family, MAL and BENE, in cervical squamous cell cancers. |
| Hatta M, Nagai H, Okino K, Onda M, Yoneyama K, Ohta Y, Nakayama H, Araki T, Emi M. |
| J Obstet Gynaecol Res. 2004 Feb;30(1):53-8. |
| PMID 14718022 |
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| Inactivation of the MAL gene in breast cancer is a common event that predicts benefit from adjuvant chemotherapy. |
| Horne HN, Lee PS, Murphy SK, Alonso MA, Olson JA Jr, Marks JR. |
| Mol Cancer Res. 2009 Feb;7(2):199-209. Epub 2009 Feb 10. |
| PMID 19208741 |
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| MAL is expressed in a subset of Hodgkin lymphoma and identifies a population of patients with poor prognosis. |
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| Cloning and characterization of MVP17: a developmentally regulated myelin protein in oligodendrocytes. |
| Kim T, Fiedler K, Madison DL, Krueger WH, Pfeiffer SE. |
| J Neurosci Res. 1995 Oct 15;42(3):413-22. |
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| Expression of mal is associated with urothelial differentiation in vitro: identification by differential display reverse-transcriptase polymerase chain reaction. |
| Liebert M, Hubbel A, Chung M, Wedemeyer G, Lomax MI, Hegeman A, Yuan TY, Brozovich M, Wheelock MJ, Grossman HB. |
| Differentiation. 1997 Feb;61(3):177-85. |
| PMID 9084136 |
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| Hypermethylated MAL gene - a silent marker of early colon tumorigenesis. |
| Lind GE, Ahlquist T, Kolberg M, Berg M, Eknaes M, Alonso MA, Kallioniemi A, Meling GI, Skotheim RI, Rognum TO, Thiis-Evensen E, Lothe RA. |
| J Transl Med. 2008 Mar 17;6:13. |
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| Clustering and lateral concentration of raft lipids by the MAL protein. |
| Magal LG, Yaffe Y, Shepshelovich J, Aranda JF, de Marco Mdel C, Gaus K, Alonso MA, Hirschberg K. |
| Mol Biol Cell. 2009 Aug;20(16):3751-62. Epub 2009 Jun 24. |
| PMID 19553470 |
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| Myelin and lymphocyte protein (MAL/MVP17/VIP17) and plasmolipin are members of an extended gene family. |
| Magyar JP, Ebensperger C, Schaeren-Wiemers N, Suter U. |
| Gene. 1997 Apr 21;189(2):269-75. |
| PMID 9168137 |
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| Expression of MAL, an integral protein component of the machinery for raft-mediated pical transport, in human epithelia. |
| Marazuela M, Acevedo A, Adrados M, Garcia-Lopez MA, Alonso MA. |
| J Histochem Cytochem. 2003 May;51(5):665-74. |
| PMID 12704214 |
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| The MAL proteolipid is a component of the detergent-insoluble membrane subdomains of human T-lymphocytes. |
| Millan J, Puertollano R, Fan L, Rancano C, Alonso MA. |
| Biochem J. 1997 Jan 1;321 (Pt 1):247-52. |
| PMID 9003426 |
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| Loss of MAL expression in precancerous lesions of the esophagus. |
| Mimori K, Nishida K, Nakamura Y, Ieta K, Yoshikawa Y, Sasaki A, Ishii H, Alonso MA, Mori M. |
| Ann Surg Oncol. 2007 May;14(5):1670-7. Epub 2006 Dec 6. |
| PMID 17151798 |
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| MAL gene expression in esophageal cancer suppresses motility, invasion and tumorigenicity and enhances apoptosis through the Fas pathway. |
| Mimori K, Shiraishi T, Mashino K, Sonoda H, Yamashita K, Yoshinaga K, Masuda T, Utsunomiya T, Alonso MA, Inoue H, Mori M. |
| Oncogene. 2003 May 29;22(22):3463-71. |
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| A genome-wide search identifies epigenetic silencing of somatostatin, tachykinin-1, and 5 other genes in colon cancer. |
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| Gastroenterology. 2006 Sep;131(3):797-808. |
| PMID 16952549 |
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| Repression of MAL tumour suppressor activity by promoter methylation during cervical carcinogenesis. |
| Overmeer RM, Henken FE, Bierkens M, Wilting SM, Timmerman I, Meijer CJ, Snijders PJ, Steenbergen RD. |
| J Pathol. 2009 Nov;219(3):327-36. |
| PMID 19662663 |
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| The MAL proteolipid is necessary for normal apical transport and accurate sorting of the influenza virus hemagglutinin in Madin-Darby canine kidney cells. |
| Puertollano R, Martin-Belmonte F, Millan J, de Marco MC, Albar JP, Kremer L, Alonso MA. |
| J Cell Biol. 1999b Apr 5;145(1):141-51. |
| PMID 10189374 |
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| Genomic structure and subcellular localization of MAL, a human T-cell-specific proteolipid protein. |
| Rancano C, Rubio T, Correas I, Alonso MA. |
| J Biol Chem. 1994b Mar 18;269(11):8159-64. |
| PMID 8132541 |
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| MARVEL: a conserved domain involved in membrane apposition events. |
| Sanchez-Pulido L, Martin-Belmonte F, Valencia A, Alonso MA. |
| Trends Biochem Sci. 2002 Dec;27(12):599-601. (REVIEW) |
| PMID 12468223 |
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| Identification of genes involved in resistance to interferon-alpha in cutaneous T-cell lymphoma. |
| Tracey L, Villuendas R, Ortiz P, Dopazo A, Spiteri I, Lombardia L, Rodriguez-Peralto JL, Fernandez-Herrera J, Hernandez A, Fraga J, Dominguez O, Herrero J, Alonso MA, Dopazo J, Piris MA. |
| Am J Pathol. 2002 Nov;161(5):1825-37. |
| PMID 12414529 |
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| A tandem array of Sp-1 sites and a reverse initiator element are both required for synergistic transcriptional activation of the T-cell-specific MAL gene. |
| Tugores A, Rubio T, Rancano C, Alonso MA. |
| DNA Cell Biol. 1997 Mar;16(3):245-55. |
| PMID 9115633 |
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| MAL mRNA is induced during the differentiation of human embryonal carcinoma cells into neurons and is also localised within specific regions of the human brain. |
| Wakeman JA, Heath PR, Pearson RC, Andrews PW. |
| Differentiation. 1997 Nov;62(2):97-105. |
| PMID 9404004 |
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| Apical trafficking in epithelial cells: signals, clusters and motors. |
| Weisz OA, Rodriguez-Boulan E. |
| J Cell Sci. 2009 Dec 1;122(Pt 23):4253-66. (REVIEW) |
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| Integrated genomic and transcriptional profiling identifies chromosomal loci with altered gene expression in cervical cancer. |
| Wilting SM, de Wilde J, Meijer CJ, Berkhof J, Yi Y, van Wieringen WN, Braakhuis BJ, Meijer GA, Ylstra B, Snijders PJ, Steenbergen RD. |
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| PMID 18618715 |
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| VIP17/MAL, a proteolipid in apical transport vesicles. |
| Zacchetti D, Peranen J, Murata M, Fiedler K, Simons K. |
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