Disease relevance of ZFYVE9

• Structure of the human cytomegalovirus protease catalytic domain reveals a novel serine protease fold and catalytic triad [1].
• Maspin, a novel serine protease inhibitor (serpin), inhibits tumor invasion and metastasis of mammary carcinoma [2].
• Identification of a novel serine protease-like gene, the expression of which is down-regulated during breast cancer progression [3].
• Maspin is a novel serine protease inhibitor (serpin) with tumor suppressive potential in breast and prostate cancer, acting at the level of tumor invasion and metastasis [4].
• We report the characterization of a novel serine protease of the chymotrypsin family, recently isolated by cDNA-representational difference analysis, as a gene overexpressed in pancreatic cancer [5].

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

• A human cDNA clone encoding a novel serine protease, cytotoxic serine protease-C(CSP-C), has been isolated from a cDNA library prepared from recombinant interleukin-2 (IL-2)-activated lymphocytes of a patient with a large granular lymphoproliferative disorder [15].

Biological context of ZFYVE9

• However, under conditions of inhibited endocytosis, Smad2 remains bound to SARA for at least 6 h without a significant decline in associated levels [16].
• Overexpression of SARA and Hgs in T cells yielded a dose-dependent decrease in cotransfected reporter gene expression, indicating an inhibitory function of both molecules [17].
• The nuclear import function of Smad2 is masked by SARA and unmasked by TGFbeta-dependent phosphorylation [18].
• SARA, a FYVE domain protein, affects Rab5-mediated endocytosis [19].
• Phosphorylation results in the release of the R-Smad from the membrane-anchored protein SARA, binding to the co-mediator protein Smad4, translocation into the nucleus, and regulation of target gene expression [20].

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

• The PCR products were subcloned and sequenced, and one of these clones was found to encode a novel serine protease, named tumor-associated differentially expressed gene-14 (TADG14) [28].
• Purification and molecular cloning of a novel serine protease from the centipede, Scolopendra subspinipes mutilans [29].
• From the control group (n=429) of the SARA study data base, 241 (161 females) never smoked, non-obese (BMI<30 kg/m2) healthy subjects aged 65-85 who were able to correctly perform at least two manoeuvres of IC were selected [30].
• Sara: her rehabilitation and its cost [31].
• SARA ratings showed a linear relation to global assessments using a visual analogue scale, suggesting linearity of the scale (p < 0.0001, r(2) = 0.98) [10].

References