Afadin Explained

Afadin is a protein that in humans is encoded by the AFDN gene.^[1]

Function

Afadin is a Ras (see HRAS; MIM 190020) target that regulates cell–cell adhesions downstream of Ras activation. It is fused with MLL (MIM 159555) in leukemias caused by t(6;11) translocations (Taya et al., 1998).[supplied by OMIM]^[2]

Interactions

Afadin has been shown to interact with:

• BCR gene,^[3]
• EPHB3,^[4]
• F11 receptor,^[5]
• HRAS and
• LMO2,^[6]
• PVRL1,^[7]
• PVRL3,^{[8] [9]}
• Profilin 1,
• RAP1A,^[10]
• RAP1GAP,^[11]
• SORBS1,^[12]
• SSX2IP,^[13]
• Tight junction protein 1,^[14] and
• USP9X.^{[15] [16]}

Further reading

• Takai Y, Nakanishi H . Nectin and afadin: novel organizers of intercellular junctions . Journal of Cell Science . 116 . Pt 1 . 17–27 . Jan 2003 . 12456712 . 10.1242/jcs.00167 . 10.1.1.321.6596 . 6465469 .
• Saha V, Lillington DM, Shelling AN, Chaplin T, Yaspo ML, Ganesan TS, Young BD . AF6 gene on chromosome band 6q27 maps distal to the minimal region of deletion in epithelial ovarian cancer . Genes, Chromosomes & Cancer . 14 . 3 . 220–2 . Nov 1995 . 8589040 . 10.1002/gcc.2870140311 . 23752846 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . Sep 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Mandai K, Nakanishi H, Satoh A, Obaishi H, Wada M, Nishioka H, Itoh M, Mizoguchi A, Aoki T, Fujimoto T, Matsuda Y, Tsukita S, Takai Y . Afadin: A novel actin filament-binding protein with one PDZ domain localized at cadherin-based cell-to-cell adherens junction . The Journal of Cell Biology . 139 . 2 . 517–28 . Oct 1997 . 9334353 . 2139800 . 10.1083/jcb.139.2.517 .
• Joh T, Yamamoto K, Kagami Y, Kakuda H, Sato T, Yamamoto T, Takahashi T, Ueda R, Kaibuchi K, Seto M . Chimeric MLL products with a Ras binding cytoplasmic protein AF6 involved in t(6;11) (q27;q23) leukemia localize in the nucleus . Oncogene . 15 . 14 . 1681–7 . Oct 1997 . 9349501 . 10.1038/sj.onc.1201332 . free .
• Saito S, Matsushima M, Shirahama S, Minaguchi T, Kanamori Y, Minami M, Nakamura Y . Complete genomic structure DNA polymorphisms, and alternative splicing of the human AF-6 gene . DNA Research . 5 . 2 . 115–20 . Apr 1998 . 9679199 . 10.1093/dnares/5.2.115 . free .
• Hock B, Böhme B, Karn T, Yamamoto T, Kaibuchi K, Holtrich U, Holland S, Pawson T, Rübsamen-Waigmann H, Strebhardt K . PDZ-domain-mediated interaction of the Eph-related receptor tyrosine kinase EphB3 and the ras-binding protein AF6 depends on the kinase activity of the receptor . Proceedings of the National Academy of Sciences of the United States of America . 95 . 17 . 9779–84 . Aug 1998 . 9707552 . 21413 . 10.1073/pnas.95.17.9779 . 1998PNAS...95.9779H . free .
• Taya S, Yamamoto T, Kano K, Kawano Y, Iwamatsu A, Tsuchiya T, Tanaka K, Kanai-Azuma M, Wood SA, Mattick JS, Kaibuchi K . The Ras target AF-6 is a substrate of the fam deubiquitinating enzyme . The Journal of Cell Biology . 142 . 4 . 1053–62 . Aug 1998 . 9722616 . 2132865 . 10.1083/jcb.142.4.1053 .
• Mandai K, Nakanishi H, Satoh A, Takahashi K, Satoh K, Nishioka H, Mizoguchi A, Takai Y . Ponsin/SH3P12: an l-afadin- and vinculin-binding protein localized at cell-cell and cell-matrix adherens junctions . The Journal of Cell Biology . 144 . 5 . 1001–17 . Mar 1999 . 10085297 . 2148189 . 10.1083/jcb.144.5.1001 .
• Linnemann T, Geyer M, Jaitner BK, Block C, Kalbitzer HR, Wittinghofer A, Herrmann C . Thermodynamic and kinetic characterization of the interaction between the Ras binding domain of AF6 and members of the Ras subfamily . The Journal of Biological Chemistry . 274 . 19 . 13556–62 . May 1999 . 10224125 . 10.1074/jbc.274.19.13556 . free .
• Takahashi K, Nakanishi H, Miyahara M, Mandai K, Satoh K, Satoh A, Nishioka H, Aoki J, Nomoto A, Mizoguchi A, Takai Y . Nectin/PRR: an immunoglobulin-like cell adhesion molecule recruited to cadherin-based adherens junctions through interaction with Afadin, a PDZ domain-containing protein . The Journal of Cell Biology . 145 . 3 . 539–49 . May 1999 . 10225955 . 2185068 . 10.1083/jcb.145.3.539 .
• Yamamoto T, Harada N, Kawano Y, Taya S, Kaibuchi K . In vivo interaction of AF-6 with activated Ras and ZO-1 . Biochemical and Biophysical Research Communications . 259 . 1 . 103–7 . May 1999 . 10334923 . 10.1006/bbrc.1999.0731 .
• Minaguchi T, Matsushima M, Saito S, Kanamori Y, Shirahama S, Okamoto S, Minami M, Taketani Y, Nakamura Y . Complete DNA sequence and characterization of a 330-kb VNTR-rich region on chromosome 6q27 that is commonly deleted in ovarian cancer . DNA Research . 6 . 2 . 131–6 . Apr 1999 . 10382971 . 10.1093/dnares/6.2.131 . free .
• Quilliam LA, Castro AF, Rogers-Graham KS, Martin CB, Der CJ, Bi C . M-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6 . The Journal of Biological Chemistry . 274 . 34 . 23850–7 . Aug 1999 . 10446149 . 10.1074/jbc.274.34.23850 . free .
• Kawabe H, Hata Y, Takeuchi M, Ide N, Mizoguchi A, Takai Y . nArgBP2, a novel neural member of ponsin/ArgBP2/vinexin family that interacts with synapse-associated protein 90/postsynaptic density-95-associated protein (SAPAP) . The Journal of Biological Chemistry . 274 . 43 . 30914–8 . Oct 1999 . 10521485 . 10.1074/jbc.274.43.30914 . free .
• Shao H, Kadono-Okuda K, Finlin BS, Andres DA . Biochemical characterization of the Ras-related GTPases Rit and Rin . Archives of Biochemistry and Biophysics . 371 . 2 . 207–19 . Nov 1999 . 10545207 . 10.1006/abbi.1999.1448 .
• Asakura T, Nakanishi H, Sakisaka T, Takahashi K, Mandai K, Nishimura M, Sasaki T, Takai Y . 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 . Genes to Cells . 4 . 10 . 573–81 . Oct 1999 . 10583506 . 10.1046/j.1365-2443.1999.00283.x . 24023429 . free .
• Miyahara M, Nakanishi H, Takahashi K, Satoh-Horikawa K, Tachibana K, Takai Y . Interaction of nectin with afadin is necessary for its clustering at cell-cell contact sites but not for its cis dimerization or trans interaction . The Journal of Biological Chemistry . 275 . 1 . 613–8 . Jan 2000 . 10617658 . 10.1074/jbc.275.1.613 . free .
• Bouchard MJ, Dong Y, McDermott BM, Lam DH, Brown KR, Shelanski M, Bellvé AR, Racaniello VR . Defects in nuclear and cytoskeletal morphology and mitochondrial localization in spermatozoa of mice lacking nectin-2, a component of cell-cell adherens junctions . Molecular and Cellular Biology . 20 . 8 . 2865–73 . Apr 2000 . 10733589 . 85510 . 10.1128/MCB.20.8.2865-2873.2000 .

Notes and References

1. Prasad R, Gu Y, Alder H, Nakamura T, Canaani O, Saito H, Huebner K, Gale RP, Nowell PC, Kuriyama K . Cloning of the ALL-1 fusion partner, the AF-6 gene, involved in acute myeloid leukemias with the t(6;11) chromosome translocation . Cancer Research . 53 . 23 . 5624–8 . Dec 1993 . 8242616 .
2. Web site: Entrez Gene: MLLT4 myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 4.
3. Radziwill G, Erdmann RA, Margelisch U, Moelling K . The Bcr kinase downregulates Ras signaling by phosphorylating AF-6 and binding to its PDZ domain . Molecular and Cellular Biology . 23 . 13 . 4663–72 . Jul 2003 . 12808105 . 164848 . 10.1128/mcb.23.13.4663-4672.2003.
4. Hock B, Böhme B, Karn T, Yamamoto T, Kaibuchi K, Holtrich U, Holland S, Pawson T, Rübsamen-Waigmann H, Strebhardt K . PDZ-domain-mediated interaction of the Eph-related receptor tyrosine kinase EphB3 and the ras-binding protein AF6 depends on the kinase activity of the receptor . Proceedings of the National Academy of Sciences of the United States of America . 95 . 17 . 9779–84 . Aug 1998 . 9707552 . 21413 . 10.1073/pnas.95.17.9779. 1998PNAS...95.9779H . free .
5. Ebnet K, Schulz CU, Meyer Zu Brickwedde MK, Pendl GG, Vestweber D . Junctional adhesion molecule interacts with the PDZ domain-containing proteins AF-6 and ZO-1 . The Journal of Biological Chemistry . 275 . 36 . 27979–88 . Sep 2000 . 10856295 . 10.1074/jbc.M002363200 . free .
6. Bégay-Müller V, Ansieau S, Leutz A . The LIM domain protein Lmo2 binds to AF6, a translocation partner of the MLL oncogene . FEBS Letters . 521 . 1–3 . 36–8 . Jun 2002 . 12067721 . 10.1016/s0014-5793(02)02814-4. 29461336 .
7. Takahashi K, Nakanishi H, Miyahara M, Mandai K, Satoh K, Satoh A, Nishioka H, Aoki J, Nomoto A, Mizoguchi A, Takai Y . Nectin/PRR: an immunoglobulin-like cell adhesion molecule recruited to cadherin-based adherens junctions through interaction with Afadin, a PDZ domain-containing protein . The Journal of Cell Biology . 145 . 3 . 539–49 . May 1999 . 10225955 . 2185068 . 10.1083/jcb.145.3.539.
8. Satoh-Horikawa K, Nakanishi H, Takahashi K, Miyahara M, Nishimura M, Tachibana K, Mizoguchi A, Takai Y . Nectin-3, a new member of immunoglobulin-like cell adhesion molecules that shows homophilic and heterophilic cell-cell adhesion activities . The Journal of Biological Chemistry . 275 . 14 . 10291–9 . Apr 2000 . 10744716 . 10.1074/jbc.275.14.10291. free .
9. Reymond N, Borg JP, Lecocq E, Adelaide J, Campadelli-Fiume G, Dubreuil P, Lopez M . Human nectin3/PRR3: a novel member of the PVR/PRR/nectin family that interacts with afadin . Gene . 255 . 2 . 347–55 . Sep 2000 . 11024295 . 10.1016/s0378-1119(00)00316-4.
10. Boettner B, Govek EE, Cross J, Van Aelst L . The junctional multidomain protein AF-6 is a binding partner of the Rap1A GTPase and associates with the actin cytoskeletal regulator profilin . Proceedings of the National Academy of Sciences of the United States of America . 97 . 16 . 9064–9 . Aug 2000 . 10922060 . 16822 . 10.1073/pnas.97.16.9064. 2000PNAS...97.9064B . free .
11. Su L, Hattori M, Moriyama M, Murata N, Harazaki M, Kaibuchi K, Minato N . AF-6 controls integrin-mediated cell adhesion by regulating Rap1 activation through the specific recruitment of Rap1GTP and SPA-1 . The Journal of Biological Chemistry . 278 . 17 . 15232–8 . Apr 2003 . 12590145 . 10.1074/jbc.M211888200 . free . 2433/148462 . free .
12. Mandai K, Nakanishi H, Satoh A, Takahashi K, Satoh K, Nishioka H, Mizoguchi A, Takai Y . Ponsin/SH3P12: an l-afadin- and vinculin-binding protein localized at cell-cell and cell-matrix adherens junctions . The Journal of Cell Biology . 144 . 5 . 1001–17 . Mar 1999 . 10085297 . 2148189 . 10.1083/jcb.144.5.1001.
13. Asada M, Irie K, Morimoto K, Yamada A, Ikeda W, Takeuchi M, Takai Y . ADIP, a novel Afadin- and alpha-actinin-binding protein localized at cell-cell adherens junctions . The Journal of Biological Chemistry . 278 . 6 . 4103–11 . Feb 2003 . 12446711 . 10.1074/jbc.M209832200 . free .
14. Yamamoto T, Harada N, Kawano Y, Taya S, Kaibuchi K . In vivo interaction of AF-6 with activated Ras and ZO-1 . Biochemical and Biophysical Research Communications . 259 . 1 . 103–7 . May 1999 . 10334923 . 10.1006/bbrc.1999.0731 .
15. Taya S, Yamamoto T, Kanai-Azuma M, Wood SA, Kaibuchi K . The deubiquitinating enzyme Fam interacts with and stabilizes beta-catenin . Genes to Cells . 4 . 12 . 757–67 . Dec 1999 . 10620020 . 10.1046/j.1365-2443.1999.00297.x. 85747886 . free .
16. Taya S, Yamamoto T, Kano K, Kawano Y, Iwamatsu A, Tsuchiya T, Tanaka K, Kanai-Azuma M, Wood SA, Mattick JS, Kaibuchi K . The Ras target AF-6 is a substrate of the fam deubiquitinating enzyme . The Journal of Cell Biology . 142 . 4 . 1053–62 . Aug 1998 . 9722616 . 2132865 . 10.1083/jcb.142.4.1053.