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Gene Review

ZFYVE9  -  zinc finger, FYVE domain containing 9

Homo sapiens

Synonyms: MADHIP, Madh-interacting protein, Mothers against decapentaplegic homolog-interacting protein, NSP, Novel serine protease, ...
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Disease relevance of ZFYVE9


Psychiatry related information on ZFYVE9

  • Sleep disorders in the elderly with and without chronic airflow obstruction: the SARA study [6].
  • Weekly efficacy assessments [Hamilton Anxiety Scale, Hospital Anxiety and Depression Scale (HADS), Self Assessment of Resilience and Anxiety (SARA)] and safety evaluations were conducted [7].
  • The SARA scale demonstrates solid psychometric properties and may serve as a reliable and valid measure in the use of kava or related medicinal herbs [8].
  • Industry response to SARA Title III: pollution prevention, risk reduction, and risk communication [9].
  • SARA score increased with the disease stage (p < 0.001) and was closely correlated with the Barthel Index (r = -0.80, p < 0.001) and part IV (functional assessment) of the Unified Huntington's Disease Rating Scale (UHDRS-IV) (r = -0.89, p < 0.0001), whereas it had only a weak correlation with disease duration (r = 0.34, p < 0.0002) [10].

High impact information on ZFYVE9

  • Here we describe the isolation of a cDNA encoding a novel serine protease that is present in HL-60 cells and is down-regulated during induced differentiation of these cells [11].
  • The Smad anchor for receptor activation (SARA) recruits Smad2 to the TGFbeta receptors for phosphorylation [12].
  • Thus, trimerization of Smad3, induced by phosphorylation, simultaneously activates the TGF-beta signal by driving Smad3 dissociation from SARA and sets up the negative feedback mechanism by Ski [13].
  • Upon phosphorylation, Smad3 dissociates from SARA and enters the nucleus, in which its transcriptional activity can be repressed by Ski [13].
  • Furthermore, c-Jun(-/-) fibroblasts exhibit enhanced association of cPML with SARA. c-Jun(-/-) fibroblasts also lose their sensitivity to TGIF-mediated disruption of the cPML-SARA complex and of nuclear sequestration of cPML [14].

Chemical compound and disease context of ZFYVE9


Biological context of ZFYVE9


Anatomical context of ZFYVE9

  • The role of internalization in transforming growth factor beta1-induced Smad2 association with Smad anchor for receptor activation (SARA) and Smad2-dependent signaling in human mesangial cells [16].
  • Th1 and Th2 cell subsets expressed the same levels of SARA and Hgs [17].
  • Not only is SARA localized on early endosomes, but also its minimal FYVE finger sequence is sufficient for early endosomal targeting [21].
  • Expression of a SARA mutant protein lacking the FYVE finger inhibits downstream activin A signaling in endothelial cells [21].
  • Consistent with this result, wortmannin, a PI3 kinase inhibitor, resulted in both a redistribution of SARA from the endosomal compartment to the cytosol and the attenuation of both TGF-beta-induced R-Smad phosphorylation and transcriptional activation [22].

Associations of ZFYVE9 with chemical compounds

  • Smad anchor for receptor activation (SARA) and hepatic growth factor-regulated tyrosine kinase substrate (Hgs) are involved in TGF-beta1 signaling [17].
  • A lipid binding assay demonstrated that the recombinant FYVE domain from SARA predominantly interacts with phosphatidylinositol 3-phosphate (PtdIns(3)P) [22].
  • MIS inhibited the proliferation of both SP and NSP cells, whereas the lipophilic chemotherapeutic agent doxorubicin more significantly inhibited the NSP cells [23].
  • By using the polymerase chain reaction, oligonucleotide primers derived from amino acids at position 14-25 and from a downstream active site conserved in other serine protease genes were used to generate a 534-base pair cDNA clone encoding a novel serine protease from RNK-16 mRNA [24].
  • It is composed of multiple polysaccharide-binding subunits associated with a novel serine protease, and its overall structural organization is similar to that of C1 [25].

Physical interactions of ZFYVE9

  • The FYVE domain in SARA directs its localization to early endosomal compartments where it can interact with both the TGF-beta receptors and Smads [16].

Enzymatic interactions of ZFYVE9

  • Additionally, SARA was found to modulate the self-association of partially phosphorylated Smad2, which suggests an added role for this protein in preventing premature release of a monophosphorylated substrate from the receptor complex [20].

Co-localisations of ZFYVE9

  • We also show that endofin co-localizes with SARA but that they are not associated in a common complex because they failed to co-immunoprecipitate in co-expressing cells [26].

Regulatory relationships of ZFYVE9

  • The TGF-beta1-stimulated association between SARA and Smad2 peaks at 30 min followed by separation of the complex components [16].

Other interactions of ZFYVE9

  • Using co-immunoprecipitation studies, we show that endogenous Smad2 interacts with SARA after TGF-beta1 stimulation [16].
  • However, the increase in SARA expression was lower (6.1+/-0.3-fold vs. 25+/-4.1-fold) compared with Smad7 and delayed, with a maximum at 12 h compared with 2 h [17].
  • Overexpressed SARA has been found on EEA1-positive early endosomes [19].
  • TGF beta signaling also requires SARA (Smad anchor for receptor activation), a 135-kD polypeptide that contains a FYVE Zn(++) finger motif [27].
  • Taken together, this report provides evidence to suggest that endofin and the highly related SARA are endosomal proteins with potential roles in regulating membrane traffic [26].

Analytical, diagnostic and therapeutic context of ZFYVE9


  1. Structure of the human cytomegalovirus protease catalytic domain reveals a novel serine protease fold and catalytic triad. Chen, P., Tsuge, H., Almassy, R.J., Gribskov, C.L., Katoh, S., Vanderpool, D.L., Margosiak, S.A., Pinko, C., Matthews, D.A., Kan, C.C. Cell (1996) [Pubmed]
  2. Maspin acts at the cell membrane to inhibit invasion and motility of mammary and prostatic cancer cells. Sheng, S., Carey, J., Seftor, E.A., Dias, L., Hendrix, M.J., Sager, R. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  3. Identification of a novel serine protease-like gene, the expression of which is down-regulated during breast cancer progression. Liu, X.L., Wazer, D.E., Watanabe, K., Band, V. Cancer Res. (1996) [Pubmed]
  4. The surface of prostate carcinoma DU145 cells mediates the inhibition of urokinase-type plasminogen activator by maspin. McGowen, R., Biliran, H., Sager, R., Sheng, S. Cancer Res. (2000) [Pubmed]
  5. A novel transmembrane serine protease (TMPRSS3) overexpressed in pancreatic cancer. Wallrapp, C., Hähnel, S., Müller-Pillasch, F., Burghardt, B., Iwamura, T., Ruthenbürger, M., Lerch, M.M., Adler, G., Gress, T.M. Cancer Res. (2000) [Pubmed]
  6. Sleep disorders in the elderly with and without chronic airflow obstruction: the SARA study. Bellia, V., Catalano, F., Scichilone, N., Incalzi, R.A., Spatafora, M., Vergani, C., Rengo, F. Sleep. (2003) [Pubmed]
  7. A placebo-controlled study of Kava kava in generalized anxiety disorder. Connor, K.M., Davidson, J.R. International clinical psychopharmacology. (2002) [Pubmed]
  8. The self-assessment of resilience and anxiety: psychometric properties. Barnett, S.D., Connor, K.M., Davidson, J.R. CNS spectrums. (2001) [Pubmed]
  9. Industry response to SARA Title III: pollution prevention, risk reduction, and risk communication. Santos, S.L., Covello, V.T., McCallum, D.B. Risk Anal. (1996) [Pubmed]
  10. Scale for the assessment and rating of ataxia: development of a new clinical scale. Schmitz-Hübsch, T., du Montcel, S.T., Baliko, L., Berciano, J., Boesch, S., Depondt, C., Giunti, P., Globas, C., Infante, J., Kang, J.S., Kremer, B., Mariotti, C., Melegh, B., Pandolfo, M., Rakowicz, M., Ribai, P., Rola, R., Schöls, L., Szymanski, S., van de Warrenburg, B.P., Dürr, A., Klockgether, T., Fancellu, R. Neurology (2006) [Pubmed]
  11. Down-regulation of a serine protease, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells. Bories, D., Raynal, M.C., Solomon, D.H., Darzynkiewicz, Z., Cayre, Y.E. Cell (1989) [Pubmed]
  12. Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Wu, G., Chen, Y.G., Ozdamar, B., Gyuricza, C.A., Chong, P.A., Wrana, J.L., Massagué, J., Shi, Y. Science (2000) [Pubmed]
  13. Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control. Qin, B.Y., Lam, S.S., Correia, J.J., Lin, K. Genes Dev. (2002) [Pubmed]
  14. Nuclear retention of the tumor suppressor cPML by the homeodomain protein TGIF restricts TGF-beta signaling. Seo, S.R., Ferrand, N., Faresse, N., Prunier, C., Abécassis, L., Pessah, M., Bourgeade, M.F., Atfi, A. Mol. Cell (2006) [Pubmed]
  15. Characterization of a novel, human cytotoxic lymphocyte-specific serine protease cDNA clone (CSP-C). Klein, J.L., Selvakumar, A., Trapani, J.A., Dupont, B. Tissue Antigens (1990) [Pubmed]
  16. The role of internalization in transforming growth factor beta1-induced Smad2 association with Smad anchor for receptor activation (SARA) and Smad2-dependent signaling in human mesangial cells. Runyan, C.E., Schnaper, H.W., Poncelet, A.C. J. Biol. Chem. (2005) [Pubmed]
  17. SARA and Hgs attenuate susceptibility to TGF-beta1-mediated T cell suppression. Kunzmann, S., Wohlfahrt, J.G., Itoh, S., Asao, H., Komada, M., Akdis, C.A., Blaser, K., Schmidt-Weber, C.B. FASEB J. (2003) [Pubmed]
  18. The nuclear import function of Smad2 is masked by SARA and unmasked by TGFbeta-dependent phosphorylation. Xu, L., Chen, Y.G., Massagué, J. Nat. Cell Biol. (2000) [Pubmed]
  19. SARA, a FYVE domain protein, affects Rab5-mediated endocytosis. Hu, Y., Chuang, J.Z., Xu, K., McGraw, T.G., Sung, C.H. J. Cell. Sci. (2002) [Pubmed]
  20. Semisynthesis of phosphovariants of Smad2 reveals a substrate preference of the activated T beta RI kinase. Ottesen, J.J., Huse, M., Sekedat, M.D., Muir, T.W. Biochemistry (2004) [Pubmed]
  21. Early endosomal regulation of Smad-dependent signaling in endothelial cells. Panopoulou, E., Gillooly, D.J., Wrana, J.L., Zerial, M., Stenmark, H., Murphy, C., Fotsis, T. J. Biol. Chem. (2002) [Pubmed]
  22. The FYVE domain in Smad anchor for receptor activation (SARA) is sufficient for localization of SARA in early endosomes and regulates TGF-beta/Smad signalling. Itoh, F., Divecha, N., Brocks, L., Oomen, L., Janssen, H., Calafat, J., Itoh, S., Dijke Pt, P. Genes Cells (2002) [Pubmed]
  23. Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Szotek, P.P., Pieretti-Vanmarcke, R., Masiakos, P.T., Dinulescu, D.M., Connolly, D., Foster, R., Dombkowski, D., Preffer, F., Maclaughlin, D.T., Donahoe, P.K. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  24. Purification and cloning of a novel serine protease, RNK-Met-1, from the granules of a rat natural killer cell leukemia. Smyth, M.J., Wiltrout, T., Trapani, J.A., Ottaway, K.S., Sowder, R., Henderson, L.E., Kam, C.M., Powers, J.C., Young, H.A., Sayers, T.J. J. Biol. Chem. (1992) [Pubmed]
  25. Substrate specificities of the protease of mouse serum Ra-reactive factor. Ogata, R.T., Low, P.J., Kawakami, M. J. Immunol. (1995) [Pubmed]
  26. Endofin, an endosomal FYVE domain protein. Seet, L.F., Hong, W. J. Biol. Chem. (2001) [Pubmed]
  27. TGF beta receptor internalization into EEA1-enriched early endosomes: role in signaling to Smad2. Hayes, S., Chawla, A., Corvera, S. J. Cell Biol. (2002) [Pubmed]
  28. Cloning of tumor-associated differentially expressed gene-14, a novel serine protease overexpressed by ovarian carcinoma. Underwood, L.J., Tanimoto, H., Wang, Y., Shigemasa, K., Parmley, T.H., O'Brien, T.J. Cancer Res. (1999) [Pubmed]
  29. Purification and molecular cloning of a novel serine protease from the centipede, Scolopendra subspinipes mutilans. You, W.K., Sohn, Y.D., Kim, K.Y., Park, D.H., Jang, Y., Chung, K.H. Insect Biochem. Mol. Biol. (2004) [Pubmed]
  30. Reference values and repeatability of inspiratory capacity for men and women aged 65-85. Tantucci, C., Pinelli, V., Cossi, S., Guerini, M., Donato, F., Grassi, V. Respiratory medicine. (2006) [Pubmed]
  31. Sara: her rehabilitation and its cost. Oliveto, M.J., Wilson, S., Mackinnon, H.A. The American journal of nursing. (1977) [Pubmed]
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