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Gene Review

ACTN4  -  actinin, alpha 4

Homo sapiens

Synonyms: ACTININ-4, Alpha-actinin-4, FSGS, FSGS1, Non-muscle alpha-actinin 4
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Disease relevance of ACTN4


High impact information on ACTN4

  • Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS [7].
  • When injected into the mesocecum of severe combined immunodeficient mice, DLD1 Tet-off ACTN4 cells, but not the control cells, metastasized into regional mesenteric lymph nodes, resembling the behavior of clinical cancers [8].
  • Upon the induction of actinin-4, DLD1 Tet-off ACTN-4 cells spread filopodia and significantly increased their motility ( P = .00027); actinin-4 protein was concentrated at the leading edges of these actin-rich podia [8].
  • A colorectal cancer cell clone capable of inducing actinin-4 using the tetracycline-regulatory system (designated DLD1 Tet-off ACTN-4) was established [8].
  • Thus, ACTN4 is a critical regulator of AKT1 localization and function [9].

Chemical compound and disease context of ACTN4


Biological context of ACTN4


Anatomical context of ACTN4


Associations of ACTN4 with chemical compounds


Physical interactions of ACTN4

  • Here we report the identification of the alpha-subunit of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and alpha-actinin-4 as potential binding partners for the densin-180 intracellular segment [26].
  • Screening of a human placenta cDNA library identified--in addition to the C-terminal region of cytokeratin 18 (CK18(182-430))--a large C-terminal fragment of alpha-actinin-4 (Act-4) as a binding partner for PAI-1 [27].

Co-localisations of ACTN4


Regulatory relationships of ACTN4

  • Attempts to demonstrate a role for NF-Y/ACTN4 in regulating CYP1A1 expression were unsuccessful, likely due to an inability to significantly change nuclear ACTN4 levels with phosphatidylinositol 3'-kinase agonists and antagonists [20].

Other interactions of ACTN4

  • No ACTN4 or WT1 mutations were detected [19].
  • CONCLUSIONS: In this study, we exhaustively analyzed the NPHS2 and the exon 8 of the ACTN4 genes in a series of sporadic 'adult-onset' FSGS patients [29].
  • There are also 3 genetic loci connected with autosomal dominant forms of FSGS: ACTN4, TRPC6 and CD2AP (found only in the mice models) [30].
  • In addition, this Ca(2+)-dependent inhibition requires Ca(2+)-dependent association between alpha-actinin-4 and E3KARP [22].
  • Non-muscle alpha-actinin-4 interacts with plasminogen activator inhibitor type-1 (PAI-1) [27].

Analytical, diagnostic and therapeutic context of ACTN4


  1. The human non-muscle alpha-actinin protein encoded by the ACTN4 gene suppresses tumorigenicity of human neuroblastoma cells. Nikolopoulos, S.N., Spengler, B.A., Kisselbach, K., Evans, A.E., Biedler, J.L., Ross, R.A. Oncogene (2000) [Pubmed]
  2. Racial and ethnic differences in the incidence and progression of focal segmental glomerulosclerosis in children. Andreoli, S.P. Advances in renal replacement therapy. (2004) [Pubmed]
  3. Podocyte proteins in Galloway-Mowat syndrome. Srivastava, T., Whiting, J.M., Garola, R.E., Dasouki, M.J., Ruotsalainen, V., Tryggvason, K., Hamed, R., Alon, U.S. Pediatr. Nephrol. (2001) [Pubmed]
  4. Mutant alpha-actinin-4 promotes tumorigenicity and regulates cell motility of a human lung carcinoma. Menez, J., Le Maux Chansac, B., Dorothée, G., Vergnon, I., Jalil, A., Carlier, M.F., Chouaib, S., Mami-Chouaib, F. Oncogene (2004) [Pubmed]
  5. Gene expression profiles of podocyte-associated molecules as diagnostic markers in acquired proteinuric diseases. Schmid, H., Henger, A., Cohen, C.D., Frach, K., Gröne, H.J., Schlöndorff, D., Kretzler, M. J. Am. Soc. Nephrol. (2003) [Pubmed]
  6. Expression and gene amplification of actinin-4 in invasive ductal carcinoma of the pancreas. Kikuchi, S., Honda, K., Tsuda, H., Hiraoka, N., Imoto, I., Kosuge, T., Umaki, T., Onozato, K., Shitashige, M., Yamaguchi, U., Ono, M., Tsuchida, A., Aoki, T., Inazawa, J., Hirohashi, S., Yamada, T. Clin. Cancer Res. (2008) [Pubmed]
  7. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Kaplan, J.M., Kim, S.H., North, K.N., Rennke, H., Correia, L.A., Tong, H.Q., Mathis, B.J., Rodríguez-Pérez, J.C., Allen, P.G., Beggs, A.H., Pollak, M.R. Nat. Genet. (2000) [Pubmed]
  8. Actinin-4 increases cell motility and promotes lymph node metastasis of colorectal cancer. Honda, K., Yamada, T., Hayashida, Y., Idogawa, M., Sato, S., Hasegawa, F., Ino, Y., Ono, M., Hirohashi, S. Gastroenterology (2005) [Pubmed]
  9. A retrovirus-based protein complementation assay screen reveals functional AKT1-binding partners. Ding, Z., Liang, J., Lu, Y., Yu, Q., Songyang, Z., Lin, S.Y., Mills, G.B. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  10. Interaction of zonula occludens-1 (ZO-1) with alpha-actinin-4: application of functional proteomics for identification of PDZ domain-associated proteins. Chen, V.C., Li, X., Perreault, H., Nagy, J.I. J. Proteome Res. (2006) [Pubmed]
  11. Treatment of the idiopathic nephrotic syndrome: regimens and outcomes in children and adults. Tune, B.M., Mendoza, S.A. J. Am. Soc. Nephrol. (1997) [Pubmed]
  12. Adding plasmapheresis to corticosteroids and alkylating agents: does it benefit patients with focal segmental glomerulosclerosis? Mitwalli, A.H. Nephrol. Dial. Transplant. (1998) [Pubmed]
  13. Collapsing and non-collapsing focal segmental glomerulosclerosis in kidney transplants. Swaminathan, S., Lager, D.J., Qian, X., Stegall, M.D., Larson, T.S., Griffin, M.D. Nephrol. Dial. Transplant. (2006) [Pubmed]
  14. Cyclosporin in the treatment of steroid-responsive and steroid-resistant nephrotic syndrome in adults. Maher, E.R., Sweny, P., Chappel, M., Varghese, Z., Moorhead, J.F. Nephrol. Dial. Transplant. (1988) [Pubmed]
  15. Analysis of mutations in alpha-actinin 4 and podocin genes of patients with chronic renal failure due to sporadic focal segmental glomerulosclerosis. Komatsuda, A., Wakui, H., Maki, N., Kigawa, A., Goto, H., Ohtani, H., Hamai, K., Oyama, Y., Makoto, H., Sawada, K., Imai, H. Renal failure. (2003) [Pubmed]
  16. The relationship among nephrin, podocin, CD2AP, and alpha-actinin might not be a true 'interaction' in podocyte. Fan, Q., Xing, Y., Ding, J., Guan, N., Zhang, J. Kidney Int. (2006) [Pubmed]
  17. Rare functional variants of podocin (NPHS2) promoter in patients with nephrotic syndrome. Oleggini, R., Bertelli, R., Di Donato, A., Di Duca, M., Caridi, G., Sanna-Cherchi, S., Scolari, F., Murer, L., Allegri, L., Coppo, R., Emma, F., Camussi, G., Perfumo, F., Ghiggeri, G.M. Gene Expr. (2006) [Pubmed]
  18. Focal and segmental glomerulosclerosis in mice with podocyte-specific expression of mutant alpha-actinin-4. Michaud, J.L., Lemieux, L.I., Dubé, M., Vanderhyden, B.C., Robertson, S.J., Kennedy, C.R. J. Am. Soc. Nephrol. (2003) [Pubmed]
  19. Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome. Sako, M., Nakanishi, K., Obana, M., Yata, N., Hoshii, S., Takahashi, S., Wada, N., Takahashi, Y., Kaku, Y., Satomura, K., Ikeda, M., Honda, M., Iijima, K., Yoshikawa, N. Kidney Int. (2005) [Pubmed]
  20. Two distinct classes of CCAAT box elements that bind nuclear factor-Y/alpha-actinin-4: potential role in human CYP1A1 regulation. Poch, M.T., Al-Kassim, L., Smolinski, S.M., Hines, R.N. Toxicol. Appl. Pharmacol. (2004) [Pubmed]
  21. Cytotoxic T lymphocytes directed against a tumor-specific mutated antigen display similar HLA tetramer binding but distinct functional avidity and tissue distribution. Echchakir, H., Dorothée, G., Vergnon, I., Menez, J., Chouaib, S., Mami-Chouaib, F. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  22. Ca(2+)-dependent inhibition of Na+/H+ exchanger 3 (NHE3) requires an NHE3-E3KARP-alpha-actinin-4 complex for oligomerization and endocytosis. Kim, J.H., Lee-Kwon, W., Park, J.B., Ryu, S.H., Yun, C.H., Donowitz, M. J. Biol. Chem. (2002) [Pubmed]
  23. High glucose and advanced glycosylated end-products affect the expression of alpha-actinin-4 in glomerular epithelial cells. Ha, T.S. Nephrology (Carlton, Vic.) (2006) [Pubmed]
  24. Renal alpha-actinin-4: purification and puromycin aminonucleoside-binding property. Goto, H., Wakui, H., Komatsuda, A., Ohtani, H., Imai, H., Sawada, K., Kobayashi, R. Nephron Exp. Nephrol. (2003) [Pubmed]
  25. {alpha}-Actinin-4 Is Required for Normal Podocyte Adhesion. Dandapani, S.V., Sugimoto, H., Matthews, B.D., Kolb, R.J., Sinha, S., Gerszten, R.E., Zhou, J., Ingber, D.E., Kalluri, R., Pollak, M.R. J. Biol. Chem. (2007) [Pubmed]
  26. Densin-180 forms a ternary complex with the (alpha)-subunit of Ca2+/calmodulin-dependent protein kinase II and (alpha)-actinin. Walikonis, R.S., Oguni, A., Khorosheva, E.M., Jeng, C.J., Asuncion, F.J., Kennedy, M.B. J. Neurosci. (2001) [Pubmed]
  27. Non-muscle alpha-actinin-4 interacts with plasminogen activator inhibitor type-1 (PAI-1). Magdolen, U., Schroeck, F., Creutzburg, S., Schmitt, M., Magdolen, V. Biol. Chem. (2004) [Pubmed]
  28. Interaction of two actin-binding proteins, synaptopodin and alpha-actinin-4, with the tight junction protein MAGI-1. Patrie, K.M., Drescher, A.J., Welihinda, A., Mundel, P., Margolis, B. J. Biol. Chem. (2002) [Pubmed]
  29. Molecular analysis of NPHS2 and ACTN4 genes in a series of 33 Italian patients affected by adult-onset nonfamilial focal segmental glomerulosclerosis. Aucella, F., De Bonis, P., Gatta, G., Muscarella, L.A., Vigilante, M., di Giorgio, G., D'Errico, M., Zelante, L., Stallone, C., Bisceglia, L. Nephron. Clinical practice [electronic resource]. (2005) [Pubmed]
  30. Genetic basis of nephrotic syndrome--review. Obeidová, H., Merta, M., Reiterová, J., Maixnerová, D., Stekrová, J., Rysavá, R., Tesar, V. Prague medical report. (2006) [Pubmed]
  31. {alpha}-Actinin 4 Potentiates Myocyte Enhancer Factor-2 Transcription Activity by Antagonizing Histone Deacetylase 7. Chakraborty, S., Reineke, E.L., Lam, M., Li, X., Liu, Y., Gao, C., Khurana, S., Kao, H.Y. J. Biol. Chem. (2006) [Pubmed]
  32. Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. Ruf, R.G., Lichtenberger, A., Karle, S.M., Haas, J.P., Anacleto, F.E., Schultheiss, M., Zalewski, I., Imm, A., Ruf, E.M., Mucha, B., Bagga, A., Neuhaus, T., Fuchshuber, A., Bakkaloglu, A., Hildebrandt, F. J. Am. Soc. Nephrol. (2004) [Pubmed]
  33. Podocyte-associated proteins FAT, alpha-actinin-4 and filtrin are expressed in Langerhans islets of the pancreas. Rinta-Valkama, J., Palmén, T., Lassila, M., Holthöfer, H. Mol. Cell. Biochem. (2007) [Pubmed]
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