The tumor suppressor Smad4/DPC 4 as a central mediator of Smad function

Zhang, Ying E.; Musci, Thomas J.; Derynck, Rik

doi:10.1016/s0960-9822(06)00123-0

Cited by 291 publications

(227 citation statements)

References 21 publications

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“…Co-transfection of Cited2 was able to enhance TGF-bmediated expression of wild-type but not MMP9 promoter mutated at the AP-1 site (Figure 6b). Smad7 and dominant negative Smad4 have been shown to inhibit Smad pathway by interfering with phosphorylation and translocation of endogenous Smads, respectively (Hayashi et al, 1997;Zhang et al, 1997). Coexpression of Smad7 or dominant negative Smad4 attenuated Cited2-mediated expression of MMP9 promoter reporter, suggesting that endogenous Smads are required for functional interaction with Cited2 to enhance MMP9 expression (Figure 6b).…”

Section: Cited2 Enhances Tgf-b-mediated Mmp9 Promoter Reporter Activitymentioning

confidence: 99%

Cited2 modulates TGF-β-mediated upregulation of MMP9

et al. 2006

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Section: Cited2 Enhances Tgf-b-mediated Mmp9 Promoter Reporter Activitymentioning

confidence: 99%

Cited2 modulates TGF-β-mediated upregulation of MMP9

et al. 2006

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“…TGF-␤, Smad2 and Smad4 translocate to the nuclei (12,20,23,28,29,33). To investigate whether phosphorylation of Ser 465 and Ser 467 in Smad2 is important for TGF-␤-dependent nuclear translocation of the Smad proteins, we used Mv1Lu cells stably transfected with wild-type Smad2 or its mutants.…”

Section: Smad2 Phosphorylation and Interaction With Smad4mentioning

confidence: 99%

“…Smad4 is a common component of TGF-␤, activin, and BMP signaling (32)(33)(34). Smad4 phosphorylation has thus far been reported only after activin stimulation of transfected cells (32).…”

mentioning

confidence: 99%

Phosphorylation of Ser465 and Ser467 in the C Terminus of Smad2 Mediates Interaction with Smad4 and Is Required for Transforming Growth Factor-β Signaling

Souchelnytskyi

Tamaki²,

Engström

et al. 1997

Journal of Biological Chemistry

369

273

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Members of the Smad family of intracellular signal transducers are essential for transforming growth factor-␤ (TGF-␤) to exert its multifunctional effects. After activation of TGF-␤ receptors, Smad2 and Smad3 become phosphorylated and form heteromeric complexes with Smad4. Thereafter, these activated Smad complexes translocate to the nucleus, where they may direct transcriptional responses. Here we report that TGF-␤ mediates phosphorylation of Smad2 at two serine residues in the C terminus, i.e. Ser 465 and Ser 467 , which are phosphorylated in an obligate order; phosphorylation of Ser 465 requires that Ser 467 be phosphorylated. Transfection of Smad2 with mutation of Ser 465 and/or Ser 467 to alanine residues into Mv1Lu cells resulted in dominantnegative inhibition of TGF-␤ signaling. These Smad2 mutants were found to stably interact with an activated TGF-␤ receptor complex, in contrast to wild-type Smad2, which interacts only transiently. Mutation of Ser 465 and Ser 467 in Smad2 abrogated complex formation of this mutant with Smad4 and blocked the nuclear accumulation not only of Smad2, but also of Smad4. Thus, heteromeric complex formation of Smad2 with Smad4 is required for nuclear translocation of Smad4. Moreover, peptides from the C terminus of Smad2 containing phosphorylated Ser 465 and Ser 467 were found to bind Smad4 in vitro, whereas the corresponding unphosphorylated peptides were less effective. Thus, phosphorylated Ser 465 and Ser 467 in Smad2 may provide a recognition site for interaction with Smad4, and phosphorylation of these sites is a key event in Smad2 activation.

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“…BMPs bind to serine-threonine kinases type I receptors (BMPRIA) and type II receptors (BMPRII) [14] that induce phosphorylation of intracellular SMADs 1, 5, or 8 at their carboxy terminus, at serine 463/465 [15]. The activated SMADs then bind to SMAD4, translocate to the nucleus, and in conjunction with specific DNA factors, activate or repress gene transcription [16]. SMAD1 can also be phosphorylated at its mid-protein linker region by activated Erk kinase (downstream of RAS), slowing or inhibiting nuclear accumulation of BMP-activated SMAD1 in mouse mammary cells [17,18].…”

Section: Introductionmentioning

confidence: 99%

BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK

Beck

Jung

Rosario

et al. 2007

Cellular Signalling

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Bone morphogenetic proteins (BMPs) regulate cell differentiation, proliferation, and apoptosis through a canonical SMAD signaling cascade. Absence of BMP signaling causes the formation of intestinal juvenile polyps in the colon cancer-prone syndrome familial juvenile polyposis. As sporadic colon cancers appear to have intact BMP signaling, we evaluated if K-RAS, driving a mitogenic pathway frequently activated in colon cancer, negatively affects BMP growth suppression. We treated non-tumorigenic but activated RAS/ERK FET cells with BMP2, and in combination with pharmacological or genetic inhibition of RAS/ERK, examined BMP-SMAD signaling, transcriptional activity, and cell growth, and also assessed p21 WAF1 mRNA, transcriptional activation, and protein levels. BMP2 increased nuclear phospho-SMAD1 2-fold, which increased another 2-3 fold when RAS/ERK was inhibited. BMP2 increased BMP-specific SMAD transcriptional activity 2-fold over control and decreased cell growth, but inhibition of RAS/ERK further enhanced BMP-specific transcriptional activity by an additional 1.5-2 fold and enhanced growth suppression by 20%. BMP-induced growth suppression is mediated in part by p21 WAF1 , not by transcriptional upregulation but by improved p21 protein stability, which is inhibited by RAS/ERK. In colon cancer cells, BMP-SMAD signaling and growth suppression is facilitated by p21 WAF1 but modulated by oncogenic K-RAS to reduce the growth suppression directed by this pathway.

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The tumor suppressor Smad4/DPC 4 as a central mediator of Smad function

Cited by 291 publications

References 21 publications

Cited2 modulates TGF-β-mediated upregulation of MMP9

Cited2 modulates TGF-β-mediated upregulation of MMP9

Phosphorylation of Ser465 and Ser467 in the C Terminus of Smad2 Mediates Interaction with Smad4 and Is Required for Transforming Growth Factor-β Signaling

BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK

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