The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase.

Kretzschmar, Marcus; Liu, Fang; Hata, Akiko; Doody, Jacqueline; Massagué, Joan

doi:10.1101/gad.11.8.984

Cited by 525 publications

(426 citation statements)

References 51 publications

Supporting

Mentioning

402

Contrasting

Unclassified

Order By: Relevance

“…Recently, phosphorylation of serine residues located in the C terminus of Smad2 was shown to be important for TGF-␤ signaling (28,31). Here we identify Ser 465 and Ser 467 as two major ligand-dependent in vivo phosphorylation sites in Smad2 and show that they are involved in the association with Smad4; mutation of these phosphorylation sites abrogates TGF-␤-induced signaling.…”

mentioning

confidence: 75%

“…2, 4, and 5). Analogously, Ser 462 in the related 462 SSVS C-terminal motif of Smad1 was recently shown to be important for BMPdependent phosphorylation of Smad1 at C-terminal serines (31). Two-dimensional maps of Smad2/S465A,S467A and Smad2/S464A,S465A,S467A mutants showed not only an expected loss of the C-terminal phosphopeptide (spot 15) but also a disappearance of most of the other acidic phosphopeptides.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas Smad1 induces ventral mesoderm, a BMP-like response, Smad2 induces dorsal mesoderm, an activin/TGF-␤-like response (22)(23)(24). Upon ligand stimulation, Smad proteins become phosphorylated on serine and threonine residues (25,26); BMP stimulates Smad1 phosphorylation (12,20,31), whereas TGF-␤ induces Smad2 and Smad3 phosphorylation (17,(27)(28)(29)(30).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

371

273

View full text Add to dashboard Cite

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.

show abstract

mentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

371

273

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…[1][2][3][4] Upon BMP ligand binding, BMPRII phosphorylates BMPRI, which in turn phosphorylates intracellular mothers against decapentaplegic, Drosophila (SMAD) 1, 5, or 8 at their C-termini. 5 The phosphorylated SMADs associate with SMAD4, and the complex translocates to the nucleus as a transcription factor to regulate the expression of various genes that control cell proliferation, cell differentiation, and apoptosis. 6 Classically, BMP ligands utilize the SMAD signaling pathway to transmit signals to the nucleus, but when SMAD4 is not present as is often seen in later stages of colon cancer development, BMP-SMAD signaling is impaired.…”

Section: Introductionmentioning

confidence: 99%

BMP suppresses PTEN expression via RAS/ERK signaling

Beck¹,

Carethers²

2007

Cancer Biology & Therapy

View full text Add to dashboard Cite

Bone morphogenetic protein (BMP), a member of the transforming growth factor β family, classically utilizes the SMAD signaling pathway for its growth suppressive effects, and loss of this signaling cascade may accelerate cell growth. In the colon cancer predisposition syndrome Juvenile Polyposis, as well as in the late progression stages of nonsyndromic colorectal cancers, SMAD4 function is typically abrogated. Here, we utilized the SMAD4-null SW480 colon cancer cell line to examine BMPs effect on a potential target gene, PTEN, and how its expression might be regulated. Initial treatment of the SMAD4-null cells with BMP resulted in mild growth suppression, but with prolonged exposure to BMP, the cells become growth stimulatory, which coincided with observed decreases in transcription and translation of PTEN, and with corresponding increases in phospho-AKT protein levels. BMP-induced PTEN suppression was mediated via the RAS/ERK pathway, as pharmacologic inhibition of RAS/ERK, or interference with protein function in the cytosol by DN-RAS prevented BMP-induced growth promotion and changes in PTEN levels, as did treatment with noggin, a BMP ligand inhibitor. Thus, BMP downregulates PTEN via RAS/ERK in a SMAD4-null environment that contributes to cell growth, and constitutes a SMAD4-independent but BMP-responsive signaling pathway.

show abstract

The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase.

Cited by 525 publications

References 51 publications

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

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

BMP suppresses PTEN expression via RAS/ERK signaling

Contact Info

Product

Resources

About