IndraLab

"In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity"

"Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3."

"Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity"

"Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3."

"SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity"

"Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3"

"Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3"

"Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain."

"We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity"

"Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity"

"Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3."

"Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3."

"We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity"

"We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function"

"Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3."

"Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3."

"In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity"

"We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity"

"Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain."

"In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity"

"Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3"

"Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3."

"Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3"

"Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3."

"Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3."

"Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity"

"Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3."

"Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity"

"SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity"

"An e3 ubiquitin ligase complex roc1-scffbw1a consisting of roc1, skp1, cullin1, and fbw1a (also termed trcp1) induces ubiquitination of smad3."

"Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation"

"Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling."

"Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases"

"Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation"

"Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblastsarkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling."

"We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function"

"We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity,"

"We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity"

"In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity"

"In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity"

"SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity"

"Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity"

"Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3"

"Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3"

"Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity"

"The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway"

"Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling."

"The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway"

"Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin."

"Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin."

"These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3."

"These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3"

"Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity."

"Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity."

"Stable expression of eid-2 in the tgf-beta1-responsive cell line inhibits endogenous smad3-smad4 complex formation and tgf-beta1-induced expression of p21 and p15. These results suggest that eid-2 may function as an endogenous suppressor of tgf-beta signaling."

"In this study, we examined the effect of eid-2 on smad-mediated tgf- signaling. Here, we show that eid-2 inhibits tgf- /smad transcriptional responses. Eid-2 interacts constitutively with smad proteins, and most strongly with smad3."

"Evi-1 interacts with smad3, an intracellular mediator of tgf-beta signalling, thereby suppressing the transcriptional activity of smad3."

"These results indicate that interaction between Smad3 and c-Jun may repress Smad3 transcriptional activity."

"Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3."

"Cki?2 Directly phosphorylates smad3 at ser418, leading to the increased ubiquitination and proteasomal degradation of activated smad3 following tgf-? Treatment."

"In this study, we show that, after tyrosine phosphorylation of p130cas mediated by integrin signaling, the phosphorylated p130cas is able to interact with phosphorylated smad3 and in turn prevent transcriptional activation by smad3"

"Through its direct interaction with smads, c-myc binds to the sp1-smad complex on the promoter of the p15(ink4b) gene, thereby inhibiting the tgf-beta-induced transcriptional activity of sp1 and smad/sp1-dependent transcription of the p15(ink4b) gene. These results suggest that oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads."

"Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation."

"The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway"

"Pkb inhibits smad3 by preventing its phosphorylation, binding to smad4 and nuclear translocation. [...] Regulation of smad3 by pkb occurs through a kinase-activity-independent mechanism, resulting in a decrease in smad3-mediated transcription and protection of cells against tgf-beta-induced apoptosis."

"Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3"

"Pkb inhibits smad3 by preventing its phosphorylation, binding to smad4 and nuclear translocation. [...] Regulation of smad3 by pkb occurs through a kinase-activity-independent mechanism, resulting in a decrease in smad3-mediated transcription and protection of cells against tgf-beta-induced apoptosis."

"Tachypacing also induced the activation of p-Smad3 (an effective mediator of TGF-β) and small-interfering RNAs for Nox2/4 attenuated its activation, supporting a crosstalk between both signalling pathways."

"The binding of TGF‐β1 to its receptor complex activates the intracellular kinase domain of TGF‐βRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non‐Smad proteins (Smad‐independent pathway)"

"Here we demonstrate that myotubularin-related protein 4"

"JNK-mediated phosphorylation of Smad3 outside the -SSXS motif enhances Smad3 nuclear translocation and potentiates transcriptional activation independent of Smad3 phosphorylation by T_RI."

"It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains"

"Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a."

"ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway"

"P38 mapk mediates fibrogenic signal through smad3 phosphorylation in rat myofibroblasts. the phosphorylation promoted hetero-complex formation and nuclear translocation of smad3 and smad4."

"Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads."

"Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads."

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"We have further shown that PIAS3, Smad3, and p300 can form a ternary complex, which is significantly increased by TGF-_ treatment. Taken together, these results suggest that PIAS3 stimulates Smad transcriptional activity through formation of a complex with Smad proteins and p300/CBP."

"Taken together, our studies indicate that on tgf-beta treatment, pias3 can form a complex with smads and p300/cbp and activate smad transcriptional activity."

"As receptor-activated smads form transcriptional complexes, they are phosphorylated at an interdomain linker region by cdk8 and cdk9, which are components of transcriptional mediator and elongation complexes. These phosphorylations promote smad transcriptional action"

"As receptor-activated smads form transcriptional complexes, they are phosphorylated at an interdomain linker region by cdk8 and cdk9, which are components of transcriptional mediator and elongation complexes. These phosphorylations promote smad transcriptional action"

"The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. Tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses."

"The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. In human hematopoietic stem/progenitor cells, where tgfbeta inhibits proliferation and stimulates erythroid differentiation, tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses."

"Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal."

"Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal."

"Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome."

"Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome."

"Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo."

"Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways."

"We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex."

"A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus"

"We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import."

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"P/caf was found to interact directly with smad3 in vitro. Moreover, smad2 and smad3 interacted with p/caf upon tgf-beta type i receptor activation in cultured mammalian cells. these results demonstrate the co-activator function of p/caf for smad2 and smad3."

"We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfb-dependent manner. the p300-dependent acetylation of smad3 was attenuated when lys19 was mutated, whereas mutation of lys20 had no effect, suggesting that lys19 is acetylated also in smad3."

"Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3."

"A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus"

"Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGF-beta type I receptor, and this oligomerization does not require Smad4"

"Here, using human and mouse breast cancer cell lines, we found that oncogene forkhead box M1 (FOXM1) interacts with SMAD3 to sustain activation of the SMAD3/SMAD4 complex in the nucleus."

"Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo."

"Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways."

"The closely related CBP and p300 proteins are also important coactivators for Smad activity. CBP and p300 act as coactivators of several transcription factors by bringing the sequence-specific activators within proximity of the general transcription machinery and by modifying the chromatin structure through histone acetylation.In response to TGF-b, Smad3 associates with CBP/p300 and TGF-b-induced C-terminal phosphorylation of Smad3 promotes this association. This association with CBP/p300 is likely to be essential for transcriptional activity of Smad3."

"BMP receptors activate Smad1, Smad5, and Smad8 (called BR-Smads in this review) whereas Smad2 and Smad3 are phosphorylated by the activin of Tgfbeta recepetors ALK3 and ALK6 can activate all three BR-Smads but ALK2 only phophorylates SMAD1 and SMAD5"

"c-Jun NH(2)-terminal kinase tended to induce the phosphorylation of Smad2/3L in human colorectal adenoma-carcinoma sequence (phosphorylation increases formation of SMAD234 complex)"

"GnRH in a dose--(0.01 to 10 microM) and time--(5 to 30 min) dependent manner decreased the rate of Smad3 activation (phospho-Smad3, pSmad3), and altered Smad3 cellular distribution in both cell types."

"TGF-B1 is the most abundant and universally expressed isoform; most studies have either examined or been performed with exogenous TGF-B1. TGF-B is secreted into the extracellular matrix as a latent protein complex bound to a latency- associated protein and one of the four isoforms of latent TGF-B binding protein. Activation of TGF-B, which is required for biologic activity, occurs through poorly understood mechanisms likely involving proteolytic processing of the associated proteins and release of the TGF-B ligand. Once activated, the TGF-B ligands regulate cellular processes by binding to three high-affinity cell surface receptors: the type I TGF-B receptor (TBRI), type II TGF-B receptor (TBRII), and type III TGF-B receptor (TBRIII, also referred to as betaglycan). Where expressed, TBRIII is the most abundant TGF-B receptor and classically functions by binding the TGF-B ligand and transferring it to its signaling receptors, TBRI and TBRII.12 TBRI and TBRII contain serine/threonine protein kinases in their intracellular domains. TBRI initiates intracellular signaling by phosphorylating a family of transcription factors, the Smads. Smad2 and Smad3 are the receptor-activated Smads for TGF-B because they are phosphorylated by TBRI. Smad4 is a common partner for all of the receptor-activated Smads. Smad6 and Smad7 are inhibitory Smads that block the phosphorylation of Smad2 or Smad3, thus inhibiting TGF-B signaling. A general mechanism for TGF-B signaling has been elucidated (Fig 1).13,14 The TGF-B ligand either binds to TBRIII, which presents TGF-B to TBRII, or binds to TBRII directly. Once bound to TGF-B, TBRII recruits, binds, and transphosphorylates TBRI, thereby stimulating its protein kinase activity. The activated TBRI phosphorylates Smad2 or Smad3, which binds to Smad4. The resulting Smad complex translocates into the nucleus and interacts in a cell specific manner with transcription factors to regulate specifically the transcription of a multitude of TGF-B responsive genes"

"BMP receptors activate Smad1, Smad5, and Smad8 (called BR-Smads in this review) whereas Smad2 and Smad3 are phosphorylated by the activin of Tgfbeta recepetors ALK3 and ALK6 can activate all three BR-Smads but ALK2 only phophorylates SMAD1 and SMAD5"

"TGF-beta phosphorylation of Smad2/3, an obligatory step of intracellular TGF-beta signaling, was also suppressed by VEGF. VEGF attenuation of TGF-beta action was also demonstrated in two other endothelial cell lines. In conclusion, VEGF attenuates TGF-beta action in the human endothelial cell, specifically at the level of transcription of PAI-1 gene and Smad2/3 phosphorylation"

"TGF-beta phosphorylation of Smad2/3, an obligatory step of intracellular TGF-beta signaling, was also suppressed by VEGF. VEGF attenuation of TGF-beta action was also demonstrated in two other endothelial cell lines. In conclusion, VEGF attenuates TGF-beta action in the human endothelial cell, specifically at the level of transcription of PAI-1 gene and Smad2/3 phosphorylation"

"TGF-B1 is the most abundant and universally expressed isoform; most studies have either examined or been performed with exogenous TGF-B1. TGF-B is secreted into the extracellular matrix as a latent protein complex bound to a latency- associated protein and one of the four isoforms of latent TGF-B binding protein. Activation of TGF-B, which is required for biologic activity, occurs through poorly understood mechanisms likely involving proteolytic processing of the associated proteins and release of the TGF-B ligand. Once activated, the TGF-B ligands regulate cellular processes by binding to three high-affinity cell surface receptors: the type I TGF-B receptor (TBRI), type II TGF-B receptor (TBRII), and type III TGF-B receptor (TBRIII, also referred to as betaglycan). Where expressed, TBRIII is the most abundant TGF-B receptor and classically functions by binding the TGF-B ligand and transferring it to its signaling receptors, TBRI and TBRII.12 TBRI and TBRII contain serine/threonine protein kinases in their intracellular domains. TBRI initiates intracellular signaling by phosphorylating a family of transcription factors, the Smads. Smad2 and Smad3 are the receptor-activated Smads for TGF-B because they are phosphorylated by TBRI. Smad4 is a common partner for all of the receptor-activated Smads. Smad6 and Smad7 are inhibitory Smads that block the phosphorylation of Smad2 or Smad3, thus inhibiting TGF-B signaling. A general mechanism for TGF-B signaling has been elucidated (Fig 1).13,14 The TGF-B ligand either binds to TBRIII, which presents TGF-B to TBRII, or binds to TBRII directly. Once bound to TGF-B, TBRII recruits, binds, and transphosphorylates TBRI, thereby stimulating its protein kinase activity. The activated TBRI phosphorylates Smad2 or Smad3, which binds to Smad4. The resulting Smad complex translocates into the nucleus and interacts in a cell specific manner with transcription factors to regulate specifically the transcription of a multitude of TGF-B responsive genes"

"c-Jun NH(2)-terminal kinase tended to induce the phosphorylation of Smad2/3L in human colorectal adenoma-carcinoma sequence (phosphorylation increases formation of SMAD234 complex)"

"Ras acting via Erk MAP kinases causes phosphorylation of Smad2 and Smad3 at specific sites in the region linking the DNA-binding domain and the transcriptional activation domain."

"The activated TGF-beta R1 phosphorylates SMAD2 and SMAD3, which bind to the SMAD4 mediator to move into the nucleus and form complexes that regulate transcription."

"Inhibition was dose-dependent on PDK1, but no inhibition was observed in the presence of an inactive kinase-dead PDK1 mutant. In addition, confocal microscopy showed that wild-type PDK1 prevents translocation of Smad3 and Smad4 from the cytoplasm to the nucleus, as well as the redistribution of Smad7 from the nucleus to the cytoplasm in response to TGF-beta. "

"PKC phosphorylates Smad2 in vivo and in vitro at Ser47 and Ser110, and Smad3 at the analogous Ser37 and Ser70 (Yakymovych et al., 2001). Phosphorylation of Smad3 by PKC blocks DNA-binding and consequently transcriptional regulation."