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)



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.

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.

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.

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]

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.

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.

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.

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.

Nuylan, M., T. Kawano, J. Inazawa, and J. Inoue. (2016). Down-regulation of LAPTM5 in human cancer cells. Oncotarget 7: 28320-28328.

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.

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.

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.

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.


TC#NameOrganismal TypeExample

Lysosomal mouse 4 TMS transporter protein, MTP, LAPTM4A (lysosomal protein transmembrane 4 alpha), LAPTM4α, of 233 aas and 4 TMSs, transports thymidine, uridine, both purine and pyrimidine nucleosides including adenosine, drugs, ionophores and steroids (Hogue et al. 1999; Li et al. 2010). LAPTM4alpha is targeted from the Golgi to late endosomes/lysosomes in a manner dependent on the E3 ubiquitin ligase Nedd4-1 and ESCRT proteins (Hirota et al. 2021).


MTP of Mus musculus


Lysosomal 4 TMS retanoic acid-inducible E3 protein.  May play a special functional role during embryogenesis and in adult hematopoietic cells (Adra et al. 1996).


E3 protein of Mus musculus


Lysosomal-associated transmembrane protein 4-beta, LAPTM4B of 317 aas and 4 TMSs.  Upregulated in many types of cancer cells, in part accounting for multidrug resistance.  Associates with P-Glycoprotein (Li et al. 2010).  May be able to flip lipids from the inner leaflet of the membrane to the outer leaflet, thereby promoting programmed cell death (Blom et al. 2015). This late endosomal protein  controls amino acid transporter interactions (Zhou et al. 2018). The ceramide-mediated regulation of LAPTM4B depends on a sphingolipid interaction motif and an adjacent aspartate residue in the protein's third transmembrane (TMS3) helix. This facilitates the interaction between LAPTM4B and the amino acid transporter heavy chain 4F2hc, thereby controlling mTORC signaling (Zhou et al. 2018). LAPTM4B regulates ceramide-induced exosome release  (Yuyama et al. 2020). (Exosomes are extracellular vesicles that mediate the transport of intracellular molecules, including neurodegenerative agents, and exogenously administrated ceramides, especially those consisting of long fatty acids, accelerate exosome production by neurons and neuroblastoma cells, inducing exosome secretion through LAPTM4B.) LAPTM4B regulates ceramide-induced exosome release (Yuyama et al. 2020) and regulates amino acid transport interactions (Zhou et al. 2018). For example, it recruits the LAT1-4F2hc Leu transporter to lysosomes (Milkereit et al. 2015). It may also facilitate late endosomal ceramide export to control cell death pathways (Blom et al. 2015). Serum LAPTM4B is a potential diagnostic and prognostic biomarker for breast cancer (Wang et al. 2022).


LAPTM4B of Homo sapiens


Lysosomal-associated transmembrane protein 5 (Lysosomal-associated multitransmembrane protein 5) (Retinoic acid-inducible E3 protein), LAPTM5, of 262 aas and 5 TMSs. It is transactivated by RUNX2 and involved in RANKL trafficking in osteoblastic cells (Geng et al. 2019). t is down regluated in human cancer cells (Nuylan et al. 2016).


LAPTM5 of Homo sapiens


Tri- or tetraspanning orphan receptor (Complement C2 receptor inhibitor tri- or tetraspanning) (SmCRIT; Sm-TOR)

AnimalsTOR of Schistosoma mansoni

Cartilage matrix protein of 672 aas, 4 N-terminal TMSs (Mtp domain) followed by a large hydrophilic domain with homology to many extracellular proteins in eukaryotes such as von Willebrand factor, integrins (TC# 8.A.54), YegL, TerY, etc. 

Mtp domain-containing matrix protein of Chelonia mydas (Green sea-turtle) (Chelonia agassizi)


Lysosomal-associated transmembrane protein 5 isoform X2 of 240 aas and 5 TM

UP of  Rousettus aegyptiacus (Egyptian rousette)


TC#NameOrganismal TypeExample

Uncharacterized protein of 165 aas and 4 TMSs  TMSs 2-4 are homologous to TMSs 2-4 and 5-7 (the two 3 TMS repeats) in TC# 2.A.74.2.6.

UP of Drosophila melanogaster (Fruit fly)


Uncharacterized protein of 196 aas and 4 TMSs.

UP of Drosophila melanogaster (Fruit fly)


Uncharacterized viral protein of 173 aas and 4 TMSs

UP of Triatoma matogrossensis


Uncharacterized protein of 185 aas and 4 TMSs.

UP of Danaus plexippus (Monarch butterfly)


Uncharacterized protein of 313 aas and 7 TMSs.

UP of Branchiostoma floridae (Florida lancelet) (Amphioxus)


Uncharacterized protein of 301 aas and 7 TMSs.  Either TMSs 1-3 are homologous to TMSs 4-6, and TMS 7 is an extra one, or TMSs 2-4 are homologous to 5-7 and TMS1 is the extra one. Maybe both are true!

UP of Branchiostoma floridae (Florida lancelet) (Amphioxus)


Uncharacterized protein of 404 aas and 6 clear peaks of hydrophobicity plus one or two small peaks preceding each set of homologous 3 TMSs.  The two repeats of 3 large TMSs are homologous to TMSs 2-4 in the 4 TMS homologue, TC# 2.A.74.2.1.

UP of Branchiostoma floridae (Florida lancelet) (Amphioxus)


Uncharacterized protein of 161 aas and 4 TMSs.

UP of Branchiostoma floridae (Florida lancelet) (Amphioxus)


Uncharacterized protein of 551 aas and 12 TMSs in a 6 + 3 + 3 TMS arrangement.

UP of Branchiostoma floridae (Florida lancelet) (Amphioxus)


Uncharacterized protein of 299 aas and 4 N-terminal TMSs

UP of Harpegnathos saltator (Jerdon's jumping ant)