Disease relevance of Smad2

• Compared with sham-operated kidneys, the level of Smad7 protein, but not mRNA, decreased progressively in UUO kidneys, whereas immunoreactivity for nuclear phosphorylated Smad2 and Smad3 and renal fibrosis were inversely increased [1].
• Compound inactivation of Smad2 in heterozygous Apc mutant mice did not change the total number of intestinal tumors but increased sudden death from intestinal obstruction caused by extremely large tumors [2].
• Perichondrium was infected with adenoviruses containing dominant-negative forms of Smad2 (Ad-Smad2-3SA) and Smad3 (Ad-Smad3 Delta C) [3].
• Mice trans-heterozygous for both Smad2 and nodal mutations display a range of phenotypes, including gastrulation defects, complex craniofacial abnormalities such as cyclopia, and defects in left-right patterning, indicating that Smad2 may mediate nodal signalling in these developmental processes [4].
• Although no mutations were detected in the Smad2 and -4 genes in tumors, proteins of Smad1 through -5 were partially or completely lost in carcinomas [5].

High impact information on Smad2

• Smad2 function is not required for mesoderm production per se, but, rather unexpectedly, in the absence of Smad2 the entire epiblast adopts a mesodermal fate giving rise to a normal yolk sac and fetal blood cells [6].
• Smad2 signals serve to restrict the site of primitive streak formation and establish anterior-posterior identity within the epiblast [6].
• In contrast, Smad2 mutants entirely lack tissues of the embryonic germ layers [6].
• Moreover, Nodal signals from the epiblast also pattern the visceral endoderm by activating the Smad2-dependent pathway required for specification of anterior identity in overlying epiblast cells [7].
• About 20 per cent of Smad2 heterozygous embryos have severe gastrulation defects and lack mandibles or eyes, indicating that the gene dosage of Smad2 is critical for signalling [4].

Chemical compound and disease context of Smad2

• DOX-induced active TGF-beta1 protein and nuclear Smad2 were restricted to cancer cells, suggesting a causal association between autocrine TGF-beta and increased metastases [8].
• Ang II stimulation caused more prominent cardiac fibrosis in ARKO mice than in WT mice with enhanced expression of types I and III collagen and transforming growth factor-beta1 genes and with increased Smad2 activation [9].
• Although this activation was most prominent at 24 h after KA administration in neurons, Smad2P immunoreactivity gradually increased in astrocytes and microglial cells at 3 and 5 days, consistent with reactive gliosis [10].
• Further, the robust induction of tubulointerstitial fibrosis without increase in activated Smad 2 levels in obstructed beta6(-/-) mice by Ang II suggests the existence of a TGF-beta1-independent pathway of induction of fibrosis through angiotensin [11].

Biological context of Smad2

• Itch promotes ubiquitination of Smad2 and augments Smad2 phosphorylation that requires an intact ligase activity of Itch [12].
• In largely Smad2-deficient chimeras, asymmetric nodal gene expression is maintained and expression of pitx2, a nodal target, is also unaffected [13].
• To examine the role of Smad2 inactivation in the process of carcinogenesis, we prepared compound heterozygous mice, which carry both Apc and Smad2 mutations on the same chromosome in the cis-configuration [2].
• Furthermore, histological examination revealed that Apc/Smad2 cis-compound heterozygotes developed multiple invasive cancers that had never been observed in Apc single heterozygotes [2].
• The results suggest that Smad2 and Smad4 might be involved in the cycling changes of mouse uterus during the oestrous cycle and embryo implantation [14].

Anatomical context of Smad2

• Moreover, introducing a human Smad3 cDNA into the mouse Smad2 locus similarly rescues anterior-posterior patterning and definitive endoderm formation and results in adult viability [15].
• Homozygous Smad2 mutant mice died around E8.5 with impaired visceral endoderm function and deficiency of mesoderm formation [2].
• Smad2-dependent signals arising in the extraembryonic tissues of early mouse embryos serve to restrict the site of primitive streak formation and establish anteroposterior identity in the epiblast [13].
• Our data suggest that Gdf11 and Smad2 regulate islet cell differentiation in parallel to the Notch pathway, which previously has been shown to control development of NGN3+ cells [16].
• Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts [17].

Associations of Smad2 with chemical compounds

• These results show that Smad2 signaling is a sensitive marker of neuronal activation and CNS injury that can be used to monitor KA-induced neuronal degeneration [10].
• We therefore used an experimental model of ovalbumin-induced allergic airway inflammation and were able to demonstrate a dramatic increase in the numbers of bronchial epithelial, alveolar, and infiltrating inflammatory cells expressing nuclear phosphorylated Smad2 within the allergen-challenged lungs [18].
• Importantly, in bleomycin-injected skin, fibroblasts showed predominantly nuclear localization of Smad3 and intense staining for phospho-Smad2/3 [19].
• During pre-implantation period, Smad2 hybridization signals were accumulated in the luminal and glandular epithelium at a basal level; Smad4 mRNA appeared in the epithelium with a little variation in hybridization signal intensity [14].
• In amifostine-treated marrows, smad 2/3 and smad4 were not detected in the nucleus but were positive in the cytoplasm of megakaryocytes 10 days after irradiation [20].

Physical interactions of Smad2

• In early Xenopus embryos, the prototypical XFast-1/Smad2/Smad4 complex ARF1 is induced at the Mix.2 ARE by activin overexpression [21].

Enzymatic interactions of Smad2

• Neither TGFbeta-dependent nor endogenously phosphorylated Smad2/3 was detectable in comparable amounts in transdifferentiated MFB, indicating loss of TGFbeta sensitivity [22].
• Endogenous Smad pathway was activated in the obstructed kidney after UUO in wild-type mice as judged by the increase of phosphorylated Smad2 or phosphorylated Smad2/3-positive cells in renal interstitial area [23].

Regulatory relationships of Smad2

• Collectively, these results demonstrate that Smad2 suppresses hepatocyte growth and dedifferentiation independent of TGF-beta signaling [24].
• Stimulation of TtT/GF cells with either TGF-beta1 or TGF-beta3 induced a rapid translocation of Smad2 into the cell nuclei [25].
• Furthermore, although Madr2 remains unlocalized in ectodermal explants, addition of activin enhances the concentration of Madr2 in the nucleus [26].

Other interactions of Smad2

• Antisense oligodeoxynucleotides were designed to attenuate Smad3 and Smad2 gene expression in embryonic (E11) mouse lungs over 4 days in culture [27].
• After implantation, on day 5 of pregnancy, Smad2 signals were localized to the subluminal stroma surrounding the implanting blastocyst, and Smad4 mRNA were accumulated in the decidua near the luminal epithelium [14].
• Previously, we excluded Smad4 and Smad2 as candidates for Par2 based on the lack of functional polymorphism(s) and differential expression in lungs from A/J and BALB/c mice [28].
• These findings suggest that the two FYVE domain proteins, Hgs and SARA, are prerequisites for receptor-mediated activation of Smad2 [29].
• These experiments provide the first evidence that TGFbeta signaling pathways are required for specification of the definitive endoderm lineage in mammals and identify Smad2 as a key mediator that directs epiblast derivatives towards an endodermal as opposed to a mesodermal fate [13].
• This acetylation event is required for the ability of Smad2 to mediate activin and TGFbeta signaling [30].

Analytical, diagnostic and therapeutic context of Smad2

• We disrupted the mouse Smad2 gene by gene targeting [2].
• RT-PCR results showed that both Smad2 and Smad4 mRNA levels were rising during peri-implantatation [14].
• In situ hybridization and semi-quantitative RT-PCR were employed to determine the temporal and spatial expression of Smad2 and Smad4 mRNA in mouse uterus during the oestrous cycle and early pregnancy [14].
• For example, use of cells deficient in Smad2 for biochemical and cell biological assays could give a better view of the function of Smad3 [31].
• Immunohistochemistry was performed, staining for TGF-beta1, -2 or -3, TGF-betaRI or -RII, Smad2, -3, -4, -6 and -7 and Smad-2P [32].

References