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Family Signaling (family + signaling)
Selected AbstractsXnr2 and Xnr5 unprocessed proteins inhibit Wnt signaling upstream of dishevelledDEVELOPMENTAL DYNAMICS, Issue 4 2005Yasuko Onuma Abstract Nodal and Nodal-related proteins activate the Activin-like signal pathway and play a key role in the formation of mesoderm and endoderm in vertebrate development. Recent studies have shown additional activities of Nodal-related proteins apart from the canonical Activin-like signal pathway. Here we report a novel function of Nodal-related proteins using cleavage mutants of Xenopus nodal-related genes (cmXnr2 and cmXnr5), which are known to be dominant-negative inhibitors of nodal family signaling. cmXnr2 and cmXnr5 inhibited both BMP signaling and Wnt signaling without activating the Activin-like signal in animal cap assays. Pro region construct of Xnr2 and Xnr5 did not inhibit Xwnt8, and pro/mature region chimera mutant cmActivin - Xnr2 and cmActivin- Xnr5 also did not inhibit Xwnt8 activity. These results indicate that the pro domains of Xnr2 and Xnr5 are necessary, but not sufficient, for Wnt inhibition, by Xnr family proteins. In addition, Western blot analysis and immunohistochemistry analysis revealed that the unprocessed Xnr5 protein is stably produced and secreted as effectively as mature Xnr5 protein, and that the unprocessed Xnr5 protein diffused in the extracellular space. These results suggest that unprocessed Xnr2 and Xnr5 proteins may be involved in inhibiting both BMP and Wnt signaling and are able to be secreted to act on somewhat distant target cells, if these are highly produced. Developmental Dynamics 234:900,910, 2005. © 2005 Wiley-Liss, Inc. [source] Turning it up a Notch: cross-talk between TGF, and Notch signalingBIOESSAYS, Issue 2 2005Michael Klüppel Signaling through both the transforming growth factor , (TGF,) superfamily of growth factors and Notch play crucial roles during embryonic pattern formation and cell fate determination. Although both pathways are able to exert similar biological responses in certain cell types, a functional interaction between these two signaling pathways has not been described. Now, three papers provide evidence of both synergy and antagonism between TGF, and Notch signaling.1,3 These reports describe a requirement for Notch signal transducers in TGF,- and BMP-induced expression of Notch target genes, as well as in BMP-controlled cell differentiation and migration. These papers uncover a direct link between the Notch and TGF, pathways and suggest a critical role for Notch in some of the biological responses to TGF, family signaling. BioEssays 27:115,118, 2005. © 2005 Wiley Periodicals, Inc. [source] Promoter-wide analysis of Smad4 binding sites in human epithelial cellsCANCER SCIENCE, Issue 11 2009Daizo Koinuma Smad4, the common partner Smad, is a key molecule in transforming growth factor-, (TGF-,) family signaling. Loss of Smad4 expression is found in several types of cancer, including pancreatic cancer and colon cancer, and is related to carcinogenesis. Here we identified Smad4 binding sites in the promoter regions of over 25 500 known genes by chromatin immunoprecipitation on a microarray (ChIP-chip) in HaCaT human keratinocytes. We identified 925 significant Smad4 binding sites. Approximately half of the identified sites overlapped the binding regions of Smad2 and Smad3 (Smad2/3, receptor-regulated Smads in TGF-, signaling), while the rest of the regions appeared dominantly occupied by Smad4 even when a different identification threshold for Smad2/3 binding regions was used. Distribution analysis showed that Smad4 was found in the regions relatively distant from the transcription start sites, while Smad2/3 binding regions were more often present near the transcription start sites. Motif analysis also revealed that activator protein 1 (AP-1) sites were especially enriched in the sites common to Smad2/3 and Smad4 binding regions. In contrast, GC-rich motifs were enriched in Smad4-dominant binding regions. We further determined putative target genes of Smad4 whose expression was regulated by TGF-,. Our findings revealed some general characteristics of Smad4 binding regions, and provide resources for examining the role of Smad4 in epithelial cells and cancer pathogenesis. (Cancer Sci 2009) [source] Regulation of TGF-, family signaling by E3 ubiquitin ligasesCANCER SCIENCE, Issue 11 2008Yasumichi Inoue Members of the transforming growth factor-, (TGF-,) family, including TGF-,, activin and bone morphogenetic proteins (BMPs), are multifunctional proteins that regulate a wide variety of cellular responses, such as proliferation, differentiation, migration and apoptosis. Alterations in their downstream signaling pathways are associated with a range of human diseases like cancer. TGF-, family members transduce signals through membrane serine/threonine kinase receptors and intracellular Smad proteins. The ubiquitin,proteasome pathway, an evolutionarily conserved cascade, tightly regulates TGF-, family signaling. In this pathway, E3 ubiquitin ligases play a crucial role in the recognition and degradation of target proteins by the 26S proteasomes. Smad degradation regulates TGF-, family signaling; HECT (homologous to the E6-accessory protein C-terminus)-type E3 ubiquitin ligases, Smad ubiquitin regulatory factor 1 (Smurf1), Smurf2, and a RING-type E3 ubiquitin ligase, ROC1-SCFFbw1a have been implicated in Smad degradation. Smurf1 and Smurf2 bind to TGF-, family receptors via the inhibitory Smads, Smad6 and Smad7, to induce their ubiquitin-dependent degradation. Arkadia, a RING-type E3 ubiquitin ligase, induces the ubiquitination and degradation of Smad7 and corepressors, c-Ski and SnoN, to enhance TGF-, family signaling. Abnormalities in E3 ubiquitin ligases that control components of TGF-, family signaling may lead to the development and progression of various cancers. (Cancer Sci 2008; 99: 2107,2112) [source] | ||||||||||