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Gene Review

MLLT4  -  myeloid/lymphoid or mixed-lineage leukemia...

Homo sapiens

Synonyms: AF-6, AF6, ALL1-fused gene from chromosome 6 protein, Afadin, Protein AF-6
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Disease relevance of MLLT4


High impact information on MLLT4

  • To understand the molecular mechanism of the specific localization of l-afadin at ZA in epithelial cells and at cell-cell AJ in nonepithelial cells, we attempted here to identify an l-afadin-binding protein(s) and isolated a protein, named ponsin [4].
  • The AF-6/afadin protein, which contains a single PDZ domain, forms a peripheral component of cell membranes at specialized sites of cell-cell junctions [5].
  • The junction-associated protein AF-6 interacts and clusters with specific Eph receptor tyrosine kinases at specialized sites of cell-cell contact in the brain [5].
  • Furthermore, AF-6 is a substrate for a subgroup of Eph receptors and phosphorylation of AF-6 is dependent on a functional kinase domain of the receptor [5].
  • Immunohistochemical analysis in the adult rat brain reveals coclustering of AF-6 with Eph receptors at postsynaptic membrane sites of excitatory synapses in the hippocampus [5].

Biological context of MLLT4


Anatomical context of MLLT4


Associations of MLLT4 with chemical compounds


Physical interactions of MLLT4

  • In this report we demonstrate that the nectin3/PRR3 receptor carries the A/EXYV consensus sequence and interacts in vivo with both long and short isoforms of afadin [6].
  • Overexpression of a truncated form of nectin-2 incapable of interacting with afadin failed to form cell-cell adhesion [14].
  • We used the yeast two-hybrid system to identify novel Lmo2 interacting proteins and found that the AF6 protein binds to Lmo2 [15].
  • In vitro binding studies using truncated fragments and their mutants suggested that SPA-1 was bound to the PDZ domain of AF-6 via probable internal PDZ ligand motif within the GAP-related domain [8].
  • Chimeric MLL products with a Ras binding cytoplasmic protein AF6 involved in t(6;11) (q27;q23) leukemia localize in the nucleus [16].

Co-localisations of MLLT4

  • Immunostaining analysis revealed that SPA-1 and RapV12 were co-localized with AF-6 at the cell attachment sites [8].

Regulatory relationships of MLLT4

  • In vivo interaction of AF-6 with activated Ras and ZO-1 [17].

Other interactions of MLLT4

  • These results suggest that the human nectin3/PRR3 is a new afadin-associated molecule [6].
  • We show here that AF-6 does not bind to human RYK in vitro or in vivo [12].
  • In the present study, we showed that SPA-1, a Rap1 GTPase-activating protein (GAP), was bound to a cytoskeleton-anchoring protein AF-6 [8].
  • Afadin, which did not bind Rap1, was inactive in this capacity [18].
  • SPA-1 and AF-6 were co-immunoprecipitated in the 293T cells transfected with both cDNAs as well as in normal thymocytes [8].
  • This can be overcome by overexpression of CSK or strong activation of c-Src. c-Src is recruited by AF-6 to cell-cell contact sites, suggesting that c-Src is regulated by a PDZ protein in special cellular locations [19].

Analytical, diagnostic and therapeutic context of MLLT4


  1. Cloning of the ALL-1 fusion partner, the AF-6 gene, involved in acute myeloid leukemias with the t(6;11) chromosome translocation. Prasad, R., Gu, Y., Alder, H., Nakamura, T., Canaani, O., Saito, H., Huebner, K., Gale, R.P., Nowell, P.C., Kuriyama, K. Cancer Res. (1993) [Pubmed]
  2. AF6 gene on chromosome band 6q27 maps distal to the minimal region of deletion in epithelial ovarian cancer. Saha, V., Lillington, D.M., Shelling, A.N., Chaplin, T., Yaspo, M.L., Ganesan, T.S., Young, B.D. Genes Chromosomes Cancer (1995) [Pubmed]
  3. Monitoring of minimal residual disease in patients with MLL-AF6-positive acute myeloid leukaemia by reverse transcriptase polymerase chain reaction. Mitterbauer, G., Zimmer, C., Pirc-Danoewinata, H., Haas, O.A., Hojas, S., Schwarzinger, I., Greinix, H., Jäger, U., Lechner, K., Mannhalter, C. Br. J. Haematol. (2000) [Pubmed]
  4. Ponsin/SH3P12: an l-afadin- and vinculin-binding protein localized at cell-cell and cell-matrix adherens junctions. Mandai, K., Nakanishi, H., Satoh, A., Takahashi, K., Satoh, K., Nishioka, H., Mizoguchi, A., Takai, Y. J. Cell Biol. (1999) [Pubmed]
  5. The junction-associated protein AF-6 interacts and clusters with specific Eph receptor tyrosine kinases at specialized sites of cell-cell contact in the brain. Buchert, M., Schneider, S., Meskenaite, V., Adams, M.T., Canaani, E., Baechi, T., Moelling, K., Hovens, C.M. J. Cell Biol. (1999) [Pubmed]
  6. Human nectin3/PRR3: a novel member of the PVR/PRR/nectin family that interacts with afadin. Reymond, N., Borg, J.P., Lecocq, E., Adelaide, J., Campadelli-Fiume, G., Dubreuil, P., Lopez, M. Gene (2000) [Pubmed]
  7. Similar and differential behaviour between the nectin-afadin-ponsin and cadherin-catenin systems during the formation and disruption of the polarized junctional alignment in epithelial cells. Asakura, T., Nakanishi, H., Sakisaka, T., Takahashi, K., Mandai, K., Nishimura, M., Sasaki, T., Takai, Y. Genes Cells (1999) [Pubmed]
  8. AF-6 controls integrin-mediated cell adhesion by regulating Rap1 activation through the specific recruitment of Rap1GTP and SPA-1. Su, L., Hattori, M., Moriyama, M., Murata, N., Harazaki, M., Kaibuchi, K., Minato, N. J. Biol. Chem. (2003) [Pubmed]
  9. Junctional adhesion molecule interacts with the PDZ domain-containing proteins AF-6 and ZO-1. Ebnet, K., Schulz, C.U., Meyer Zu Brickwedde, M.K., Pendl, G.G., Vestweber, D. J. Biol. Chem. (2000) [Pubmed]
  10. The Bcr kinase downregulates Ras signaling by phosphorylating AF-6 and binding to its PDZ domain. Radziwill, G., Erdmann, R.A., Margelisch, U., Moelling, K. Mol. Cell. Biol. (2003) [Pubmed]
  11. Defects in nuclear and cytoskeletal morphology and mitochondrial localization in spermatozoa of mice lacking nectin-2, a component of cell-cell adherens junctions. Bouchard, M.J., Dong, Y., McDermott, B.M., Lam, D.H., Brown, K.R., Shelanski, M., Bellvé, A.R., Racaniello, V.R. Mol. Cell. Biol. (2000) [Pubmed]
  12. RYK, a catalytically inactive receptor tyrosine kinase, associates with EphB2 and EphB3 but does not interact with AF-6. Trivier, E., Ganesan, T.S. J. Biol. Chem. (2002) [Pubmed]
  13. Identification of Ce-AF-6, a novel Caenorhabditis elegans protein, as a putative Ras effector. Watari, Y., Kariya, K., Shibatohge, M., Liao, Y., Hu, C.D., Goshima, M., Tamada, M., Kikuchi, A., Kataoka, T. Gene (1998) [Pubmed]
  14. Restoration of E-cadherin-based cell-cell adhesion by overexpression of nectin in HSC-39 cells, a human signet ring cell gastric cancer cell line. Peng, Y.F., Mandai, K., Nakanishi, H., Ikeda, W., Asada, M., Momose, Y., Shibamoto, S., Yanagihara, K., Shiozaki, H., Monden, M., Takeichi, M., Takai, Y. Oncogene (2002) [Pubmed]
  15. The LIM domain protein Lmo2 binds to AF6, a translocation partner of the MLL oncogene. Bégay-Müller, V., Ansieau, S., Leutz, A. FEBS Lett. (2002) [Pubmed]
  16. Chimeric MLL products with a Ras binding cytoplasmic protein AF6 involved in t(6;11) (q27;q23) leukemia localize in the nucleus. Joh, T., Yamamoto, K., Kagami, Y., Kakuda, H., Sato, T., Yamamoto, T., Takahashi, T., Ueda, R., Kaibuchi, K., Seto, M. Oncogene (1997) [Pubmed]
  17. In vivo interaction of AF-6 with activated Ras and ZO-1. Yamamoto, T., Harada, N., Kawano, Y., Taya, S., Kaibuchi, K. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  18. Regulation of E-cadherin endocytosis by nectin through afadin, Rap1, and p120ctn. Hoshino, T., Sakisaka, T., Baba, T., Yamada, T., Kimura, T., Takai, Y. J. Biol. Chem. (2005) [Pubmed]
  19. Regulation of c-Src by binding to the PDZ domain of AF-6. Radziwill, G., Weiss, A., Heinrich, J., Baumgartner, M., Boisguerin, P., Owada, K., Moelling, K. EMBO J. (2007) [Pubmed]
  20. Chronic eosinophilic leukemia with t(6;11)(q27;q23) translocation. Suzuki, S., Chiba, K., Toyoshima, N., Kurosawa, M., Hashino, S., Musashi, M., Asaka, M. Ann. Hematol. (2001) [Pubmed]
  21. ML-1 cell line lacks a germline MLL locus. Strout, M.P., Mrózek, K., Heinonen, K., Sait, S.N., Shows, T.B., Aplan, P.D. Genes Chromosomes Cancer (1996) [Pubmed]
  22. Molecular analysis of the rearranged genome and chimeric mRNAs caused by the t(6;11)(q27;q23) chromosome translocation involving MLL in an infant acute monocytic leukemia. Akao, Y., Isobe, M. Genes Chromosomes Cancer (2000) [Pubmed]
  23. Monitoring minimal residual disease in patients with MLL-AF6 fusion transcript-positive acute myeloid leukemia following allogeneic bone marrow transplantation. Takatsuki, H., Yufu, Y., Tachikawa, Y., Uike, N. Int. J. Hematol. (2002) [Pubmed]
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