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2.A.74. The 4 TMS Multidrug Endosomal Transporter (MET) Family

The proteins of the MET family have been sequenced and characterized from mouse and humans. The two orthologues from mouse and man have the same length and sequence, but these two organisms have paralogues of dissimilar sequence. Some are upregulated in cancer cells (Shao et al. 2003).  Distant homologues are present in C. elegans, D. melanogaster and Schistosoma mansoni. Most of these proteins are of 233-262 amino acyl residues in length and exhibit 4 TMSs. However, the Drosophilia protein is much larger (749 aas), and the region of sequence similarity encompasses residues 447-606. The homologue in S. mansoni (AF051138; 281aas) is called the trispanning orphan receptor, TorE. The two functionally characterized human and mouse orthologues are located in late endosomal, golgi and/or lysosomal membranes (Adra et al. 1996). Their transcripts are expressed in most if not all tissues and cell types. The C-termini of these proteins possess hydrophilic domains containing several tyrosine-based sorting motifs YXXHy, where Hy represents a bulky hydrophobic residue. This sequence directs proteins to intracellular compartments in eukaryotes. Substrates of the mouse MET (also called 'mouse transporter protein,' MTP) include thymidine, both nucleoside and nucleobase analogues, antibiotics, anthracyclines, ionophores and steroid hormones (Hogue et al. 1999). MET transporters may be involved in the subcellular compartmentation of steroid hormones and other compounds (Li et al. 2010).

Drug sensitivity by mouse MET is regulated by compounds that inhibit lysosomal function, interface with intracellular cholesterol transport, or modulate the multidrug resistance phenotype of mammalian cells (Li et al. 2010). Thus, MET family members may compartmentalize diverse hydrophobic molecules, thereby affecting cellular drug sensitivity, nucleoside/nucleobase availability and steroid hormone responses.  At least one member of the family (LAPTM4B; 2.A.74.1.3) may also catalyze or promote catalysis of llipid flipping from one lieaflet to the other leaflet of a bilayer (Blom et al. 2015).

A related protein is the retinoic acid-inducible E3 protein associated with liposomes of lymphoid and myeloid tissues of the mouse (Adra et al. 1996). The E3 protein consists of 261 amino acid and exhibits 5 putative TMSs. Both MTP and the E3 protein have human homologues. Several INT family paralogues are found in the completely sequenced genome of C. elegans. The mode of transport and energy coupling mechanism, if any, have not been investigated, but a proton antiport mechanism is inferred.

The generalized transport reaction catalyzed by MTP is presumed to be:

nucleoside or hydrophobic compound (cytoplasm) + nH+ (lysosomal or endosomal lumen) ⇌ nucleoside or hydrophobic compound (lysosomal or endosomal lumen) + nH+ (cytoplasm)

References associated with 2.A.74 family:

Adra, C.N., S. Zhu, J.L. Ko, J.C. Guillemot, A.M. Cuervo, H. Kobayashi, T. Horiuchi, J.M. Lelias, J.D. Rowley, and B. Lim. (1996). LAPTM5: a novel lysosomal-associated multispanning membrane protein preferentially expressed in hematopoietic cells. Genomics 35: 328-337. 8661146
Blom, T., S. Li, A. Dichlberger, N. Bäck, Y.A. Kim, U. Loizides-Mangold, H. Riezman, R. Bittman, and E. Ikonen. (2015). LAPTM4B facilitates late endosomal ceramide export to control cell death pathways. Nat Chem Biol 11: 799-806. 26280656
Geng, Y.M., C.X. Liu, W.Y. Lu, P. Liu, P.Y. Yuan, W.L. Liu, P.P. Xu, and X.Q. Shen. (2019). LAPTM5 is transactivated by RUNX2 and involved in RANKL trafficking in osteoblastic cells. Mol Med Rep 20: 4193-4201. 31545469
Hirota, Y., M. Hayashi, Y. Miyauchi, Y. Ishii, Y. Tanaka, and K. Fujimoto. (2021). LAPTM4α is targeted from the Golgi to late endosomes/lysosomes in a manner dependent on the E3 ubiquitin ligase Nedd4-1 and ESCRT proteins. Biochem. Biophys. Res. Commun. 556: 9-15. [Epub: Ahead of Print] 33836347
Hogue, D.L., L. Kerby, and V. Ling. (1999). A mammalian lysosomal membrane protein confers multidrug resistance upon expression in Saccharomyces cerevisiae. J. Biol. Chem. 274: 12877-12882. 10212276
Hogue, D.L., M.J. Ellison, J.D. Young, and C.E. Cass. (1996). Identification of a novel membrane transporter associated with intracellular membranes by phenotypic complementation in the yeast Saccharomyces cerevisiae. J. Biol. Chem. 271: 9801-9808. 8621662
Li, L., X.H. Wei, Y.P. Pan, H.C. Li, H. Yang, Q.H. He, Y. Pang, Y. Shan, F.X. Xiong, G.Z. Shao, and R.L. Zhou. (2010). LAPTM4B: a novel cancer-associated gene motivates multidrug resistance through efflux and activating PI3K/AKT signaling. Oncogene 29: 5785-5795. 20711237
Milkereit, R., A. Persaud, L. Vanoaica, A. Guetg, F. Verrey, and D. Rotin. (2015). LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation. Nat Commun 6: 7250. 25998567
Nuylan, M., T. Kawano, J. Inazawa, and J. Inoue. (2016). Down-regulation of LAPTM5 in human cancer cells. Oncotarget 7: 28320-28328. 27058622
Shao, G.Z., R.L. Zhou, Q.Y. Zhang, Y. Zhang, J.J. Liu, J.A. Rui, X. Wei, and D.X. Ye. (2003). Molecular cloning and characterization of LAPTM4B, a novel gene upregulated in hepatocellular carcinoma. Oncogene 22: 5060-5069. 12902989
Wang, L., Y. Wang, and Q. Zhang. (2022). Serum LAPTM4B as a Potential Diagnostic and Prognostic Biomarker for Breast Cancer. Biomed Res Int 2022: 6786351. 36506911
Yuyama, K., H. Sun, D. Mikami, T. Mioka, K. Mukai, and Y. Igarashi. (2020). Lysosomal-associated transmembrane protein 4B regulates ceramide-induced exosome release. FASEB J. 34: 16022-16033. 33090522
Zhou, K., A. Dichlberger, H. Martinez-Seara, T.K.M. Nyholm, S. Li, Y.A. Kim, I. Vattulainen, E. Ikonen, and T. Blom. (2018). A Ceramide-Regulated Element in the Late Endosomal Protein LAPTM4B Controls Amino Acid Transporter Interaction. ACS Cent Sci 4: 548-558. 29806001