Smad6 functions as an intracellular antagonist of some TGF‐β family members during <i>Xenopus</i> embryogenesis

Nakayama, Takuya; Gardner, Holly; Berg, Linnea; Christian, Jan L.

doi:10.1046/j.1365-2443.1998.00196.x

Cited by 75 publications

(67 citation statements)

References 21 publications

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“…To confirm inhibiting BMP signaling during the later patterning of the renal field results in the malformation of the pronephric tubules and duct, but does not alter glomal tissue, we next took advantage of an additional inducible construct (ERSmad6) previously shown to conditionally inhibit BMP signaling in vivo (Nakayama et al, 1998;Ishisaki et al, 1999;Schmerer and Evans, 2003). Analogous to the ⌬Smad7 construct described above, another protein that specifically regulates BMP signaling is the Smad6 transcriptional cofactor.…”

Section: Conditional Regulation Of the Inhibitory-smad Smad6 Also Rmentioning

confidence: 99%

Patterning the embryonic kidney: BMP signaling mediates the differentiation of the pronephric tubules and duct in Xenopus laevis

Bracken

Mizeracka

McLaughlin

2007

Developmental Dynamics

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The Bone morphogenetic proteins (BMPs) mediate a wide range of diverse cellular behaviors throughout development. Previous studies implicated an important role for BMP signaling during the differentiation of the definitive mammalian kidney, the metanephros. In order to examine whether BMP signaling also plays an important role during the patterning of earlier renal systems, we examined the development of the earliest nephric system, the pronephros. Using the amphibian model system Xenopus laevis, in combination with reagents designed to inhibit BMP signaling during specific stages of nephric development, we revealed an evolutionarily conserved role for this signaling pathway during renal morphogenesis. Our results demonstrate that conditional BMP inhibition after specification of the pronephric anlagen is completed, but prior to the onset of morphogenesis and differentiation of renal tissues, results in the severe malformation of both the pronephric duct and tubules. Importantly, the effects of BMP signaling on the developing nephron during this developmental window are specific, only affecting the developing duct and tubules, but not the glomus. These data, combined with previous studies examining metanephric development in mice, provide further support that BMP functions to mediate morphogenesis of the specified renal field during vertebrate embryogenesis. Specifically, BMP signaling is required for the differentiation of two types of nephric structures, the pronephric tubules and duct. Developmental Dynamics 237:132-144, 2008.

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Section: Conditional Regulation Of the Inhibitory-smad Smad6 Also Rmentioning

confidence: 99%

Patterning the embryonic kidney: BMP signaling mediates the differentiation of the pronephric tubules and duct in Xenopus laevis

Bracken

Mizeracka

McLaughlin

2007

Developmental Dynamics

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“…Three bone-inducing LMP variants (LMP-1, LMP1t, and LMP-3) each contain a unique 45-amino acid peptide sequence that includes two putative Smurf1 WW domain interaction sites (A and B) (Fig. 2a) (29). The WW domain-interacting sites are absent in the nonosteogenic LMP variant (LMP-2).…”

Section: Determination Of the Domains Of Lmp-1 And Smurf1 That Are Inmentioning

confidence: 99%

LIM Mineralization Protein-1 Potentiates Bone Morphogenetic Protein Responsiveness via a Novel Interaction with Smurf1 Resulting in Decreased Ubiquitination of Smads

Sangadala

Boden

Viggeswarapu

et al. 2006

Journal of Biological Chemistry

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Development and repair of the skeletal system and other organs is highly dependent on precise regulation of bone morphogenetic proteins (BMPs), their receptors, and their intracellular signaling proteins known as Smads. The use of BMPs clinically to induce bone formation has been limited in part by the requirement of much higher doses of recombinant proteins in primates than were needed in cell culture or rodents. Therefore, control of cellular responsiveness to BMPs is now a critical area that is poorly understood. We determined that LMP-1, a LIM domain protein capable of inducing de novo bone formation, interacts with Smurf1 (Smad ubiquitin regulatory factor 1) and prevents ubiquitination of Smads. In the region of LMP responsible for bone formation, there is a motif that directly interacts with the Smurf1 WW2 domain and can effectively compete with Smad1 and Smad5 for binding. We have shown that small peptides containing this motif can mimic the ability to block Smurf1 from binding Smads. This novel interaction of LMP-1 with the WW2 domain of Smurf1 to block Smad binding results in increased cellular responsiveness to exogenous BMP and demonstrates a novel regulatory mechanism for the BMP signaling pathway.Bone morphogenetic proteins are critical regulators of osteoblast differentiation and bone formation (1). BMPs 2 were originally identified as molecules that could induce ectopic bone and cartilage formation in rodents (2). Subsequently, various members of the BMP family have been shown to play a role in development of limb bud patterning, kidney, germ cells, nervous system elements, tendons/ligaments, and control of apoptosis (3). Several members of the BMP family are osteoinductive and able to induce the differentiation of mesenchymal cells into osteoblasts (4). The various activities of the BMPs are modulated through the control of antagonists, cell surface receptors, intracellular signaling proteins (Smads), and cross-talk with other signaling pathways (5, 6). Clinically, rhBMP-2 is being used to achieve spine fusion in patients with low back pain and avoids the morbidity of bone harvested from the pelvis (7,8). Unfortunately, without improving the responsiveness to BMP-2, the high doses (milligrams) required in humans and the resultant cost are prohibitive for routine clinical use (9).BMP responsiveness is dependent in part on the availability of intracellular signaling proteins. When activated, the type I BMP receptors phosphorylate intracellular mediators, the Smad proteins (10). The receptor-regulated Smads (R-Smads) are phosphorylated by the type I receptors upon ligand binding (11). Smad2 and Smad3 are involved in the TGF-␤/activin pathway, whereas Smads 1, 5, and 8 act in response to BMPs (12). The phosphorylated R-Smads interact with the single common Smad, Smad4, forming a complex that translocates into the nucleus, associates with DNA, and is responsible for transcriptional regulation of target genes (13).To examine strategies for improving cellular responsiveness to BMPs, we chose to study hu...

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“…Recently, a distinct subgroup of distantly related Smads, including mammalian Smad6 (23) and Smad7 (24,25), Xenopus Smad6 (XSmad6) (26) and Smad8 (now called XSmad7) (27) and Drosophila Dad (28), have been identified as intracellular antagonists of TGF-␤ family signaling. Smad6 and Smad7 form stable associations with activated TGF-␤ type I receptor (T␤R-I), thereby preventing pathway restricted Smads from binding to, and being phosphorylated by, these receptors.…”

Section: Members Of the Transforming Growth Factor-␤ (Tgf-␤)mentioning

confidence: 99%

“…Smad6 has also been shown to bind to and inhibit signaling downstream of BMP receptors (23) and to prevent formation of an active Smad4/Smad1 signaling complex by directly competing with Smad4 for binding to Smad1 (29). In Xenopus embryos, ectopically expressed murine Smad7 (mSmad7), XSmad7, or XSmad6 can partially antagonize activin-like signaling although both are much more potent inhibitors of BMPs (25)(26)(27)29). Inhibitory Smads, like signal-transducing Smads, contain conserved N-and C-domains, but the function of each domain is unknown.…”

Section: Members Of the Transforming Growth Factor-␤ (Tgf-␤)mentioning

confidence: 99%

Physical and Functional Interaction of Murine and Xenopus Smad7 with Bone Morphogenetic Protein Receptors and Transforming Growth Factor-β Receptors

Souchelnytskyi¹,

Nakayama²,

Nakao³

et al. 1998

Journal of Biological Chemistry

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119

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Members of the transforming growth factor-␤ (TGF-␤)family transmit signals from membrane to nucleus via intracellular proteins known as Smads. A subclass of Smad proteins has recently been identified that antagonize, rather than transduce, TGF-␤ family signals. Smad7, for example, binds to and inhibits signaling downstream of TGF-␤ receptors. Here we report that the C-terminal MAD homology domain of murine Smad7 (mSmad7) is sufficient for both of these activities. In addition, we show that mSmad7 interacts with activated bone morphogenetic protein (BMP) type I receptors (BMPR-Is), inhibits BMPR-I-mediated Smad phosphorylation, and phenocopies the effect of known BMP antagonists when overexpressed in ventral cells of Xenopus embryos. Xenopus Smad7 (XSmad7, previously termed Smad8) and mSmad7 are nearly identical within their bioactive C-domain, but have quite distinct Ndomains. We found that XSmad7, similar to mSmad7, interacted with BMP and TGF-␤ type I receptors and inhibited receptor-mediated phosphorylation of downstream signal-transducing Smads. However, XSmad7 is a less efficient inhibitor of T␤R-I-mediated responses in mammalian cells than is mSmad7. Furthermore, overexpression of XSmad7 in Xenopus embryos produces patterning defects that are not observed following overexpression of mSmad7, suggesting that mSmad7 and XSmad7 may preferentially target distinct signaling pathways. Our results are consistent with the possibility that the C-domain of antagonistic Smads is an effector domain whereas the N-domain may confer specificity for distinct signaling pathways.

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Smad6 functions as an intracellular antagonist of some TGF‐β family members during Xenopus embryogenesis

Cited by 75 publications

References 21 publications

Patterning the embryonic kidney: BMP signaling mediates the differentiation of the pronephric tubules and duct in Xenopus laevis

Patterning the embryonic kidney: BMP signaling mediates the differentiation of the pronephric tubules and duct in Xenopus laevis

LIM Mineralization Protein-1 Potentiates Bone Morphogenetic Protein Responsiveness via a Novel Interaction with Smurf1 Resulting in Decreased Ubiquitination of Smads

Physical and Functional Interaction of Murine and Xenopus Smad7 with Bone Morphogenetic Protein Receptors and Transforming Growth Factor-β Receptors

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