Transforming Growth Factor β Depletion Is the Primary Determinant of Smad Signaling Kinetics

Clarke, David; Brown, Meredith L.; Erickson, Richard A.; Shi, Yigong; Liu, Xuedong

doi:10.1128/mcb.01443-08

Cited by 59 publications

(75 citation statements)

References 60 publications

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“…Smad2/3 was phosphorylated in response to Ads-TGF stimulation for the initial 4 days of culture, whereas Med-TGF generated phosphorylated Smad2/3 for the entire 3 weeks of culture. Given the wide diversity of cell functions controlled by TGF-b1 signaling 18,19 and the importance of TGF-b1 signal duration, dynamic reversible Smad phosphorylation, and ligand depletion kinetics in determining outcome, [46][47][48] tuning the delivery duration and dose for prochondrogenic growth factors will likely be critical to the success of BMSC-based cartilage resurfacing technologies.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study highlighted the importance of TGF-b1 signaling duration in determining cellular response by showing that endothelial cells sense TGF-b1 dose by depleting it through constitutive receptor trafficking processes. 48 In addition, tumor cells with impaired receptor trafficking led to TGF-b1 overproduction, which correlated with a poor disease prognosis. Thus, TGFb1 signaling duration can have a significant impact on cell decisions and function.…”

Section: Controlled Delivery Of Tgf-b1 By Self-assembling Peptidesmentioning

confidence: 99%

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Controlled Delivery of Transforming Growth Factor β1 by Self-Assembling Peptide Hydrogels Induces Chondrogenesis of Bone Marrow Stromal Cells and Modulates Smad2/3 Signaling

Kopesky

Vanderploeg²,

Kisiday

et al. 2011

Tissue Engineering Part A

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Self-assembling peptide hydrogels were modified to deliver transforming growth factor b1 (TGF-b1) to encapsulated bone-marrow-derived stromal cells (BMSCs) for cartilage tissue engineering applications using two different approaches: (i) biotin-streptavidin tethering; (ii) adsorption to the peptide scaffold. Initial studies to determine the duration of TGF-b1 medium supplementation necessary to stimulate chondrogenesis showed that 4 days of transient soluble TGF-b1 to newborn bovine BMSCs resulted in 10-fold higher proteoglycan accumulation than TGF-b1-free culture after 3 weeks. Subsequently, BMSC-seeded peptide hydrogels with either tethered TGF-b1 (Teth-TGF) or adsorbed TGF-b1 (Ads-TGF) were cultured in the TGF-b1-free medium, and chondrogenesis was compared to that for BMSCs encapsulated in unmodified peptide hydrogels, both with and without soluble TGF-b1 medium supplementation. Ads-TGF peptide hydrogels stimulated chondrogenesis of BMSCs as demonstrated by cell proliferation and cartilage-like extracellular matrix accumulation, whereas Teth-TGF did not stimulate chondrogenesis. In parallel experiments, TGF-b1 adsorbed to agarose hydrogels stimulated comparable chondrogenesis. Full-length aggrecan was produced by BMSCs in response to Ads-TGF in both peptide and agarose hydrogels, whereas medium-delivered TGF-b1 stimulated catabolic aggrecan cleavage product formation in agarose but not peptide scaffolds. Smad2/3 was transiently phosphorylated in response to Ads-TGF but not Teth-TGF, whereas medium-delivered TGF-b1 produced sustained signaling, suggesting that dose and signal duration are potentially important for minimizing aggrecan cleavage product formation. Robustness of this technology for use in multiple species and ages was demonstrated by effective chondrogenic stimulation of adult equine BMSCs, an important translational model used before the initiation of human clinical studies.

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Section: Discussionmentioning

confidence: 99%

Section: Controlled Delivery Of Tgf-b1 By Self-assembling Peptidesmentioning

confidence: 99%

Controlled Delivery of Transforming Growth Factor β1 by Self-Assembling Peptide Hydrogels Induces Chondrogenesis of Bone Marrow Stromal Cells and Modulates Smad2/3 Signaling

Kopesky

Vanderploeg²,

Kisiday

et al. 2011

Tissue Engineering Part A

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“…An in vitro kinetic analysis of TGF ligand bioavailability has shown that constitutive endocytosis of TRII depletes excess ligand (Clarke et al, 2009). This mechanism enables a cell to fine-tune the level of signaling growth factor on the cell surface.…”

Section: Tgf Receptor Regulation and Endocytosismentioning

confidence: 99%

The regulation of TGFβ signal transduction

2009

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Transforming growth factor  (TGF) pathways are implicated in metazoan development, adult homeostasis and disease. TGF ligands signal via receptor serine/threonine kinases that phosphorylate, and activate, intracellular Smad effectors as well as other signaling proteins. Oligomeric Smad complexes associate with chromatin and regulate transcription, defining the biological response of a cell to TGF family members. Signaling is modulated by negative-feedback regulation via inhibitory Smads. We review here the mechanisms of TGF signal transduction in metazoans and emphasize events crucial for embryonic development. IntroductionThe human transforming growth factor  (TGF) family consists of 33 members, most of which encode dimeric, secreted polypeptides that control developmental processes, ranging from gastrulation and body axis asymmetry to organ-specific morphogenesis and adult tissue homeostasis (reviewed by Derynck and Miyazono, 2008). In addition to TGFs, this family includes the bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins and nodal. The TGF family is conserved throughout metazoan evolution. At the cellular level, TGF family members regulate cell growth, differentiation, adhesion, migration and death, in a developmental context-dependent and cell type-specific manner. For example, TGF more often inhibits, but sometimes also stimulates, cell proliferation (reviewed by Yang and Moses, 2008). Furthermore, nodal signaling sometimes inhibits, whereas BMP promotes, cell differentiation, as in stem cells (Watabe and Miyazono, 2009). As TGF ligands act multifunctionally in numerous tissue types, they also play complex roles in various human diseases, ranging from autoimmune to cardiovascular diseases and cancer (reviewed by Gordon and Blobe, 2008;Massagué, 2008).Here we review the core components of the TGF family and their signaling engines, as part of a Minifocus in this issue on TGF signaling (see Box 1), and discuss emerging concepts concerning the regulatory mechanisms of TGF pathways at the receptor, cytoplasmic and nuclear level. We also highlight recent discoveries that are of particular developmental relevance. The TGF familyThe development of the axes and the asymmetry of the animal body depends on the localized action of extracellular signals, such as the Wnt, nodal and BMP ligands. Gradients of these ligands, their extracellular regulators and the competence of receptors in responding cells, play important roles during tissue morphogenesis (Affolter and Basler, 2007;Smith and Gurdon, 2004). TGF family members also contribute to tissue patterning and are important regulators of stem cell self-renewal and differentiation (see Box 2) (De Robertis and Kuroda, 2004;Watabe and Miyazono, 2009).The TGF morphogens include numerous secreted and conserved polypeptides (Table 1), which emerged at the onset of multicellular (metazoan) life (Huminiecki et al., 2009). Structurally, this family is characterized by a specific three-dimensional fold and by a conser...

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“…The phosphorylated Smad2/3 then associate with Smad4 and translocate into the nucleus, where together with other transcription factors they positively and negatively regulate the transcription of a large array of target genes in a cell contextdependent manner (7, 12, 14, 18 -21). In general, endocytosis regulates receptor cell surface levels of various receptors, potentially affecting signaling output (22)(23)(24)(25)(26)(27)(28)(29)(30). Studies on the endocytosis of active T␤RI and T␤RII were hampered by the inability to use iodinated TGF-␤ to follow their internalization, which is masked by the abundance of receptors and extracellular matrix-associated proteins that bind the ligand.…”

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confidence: 99%

Coated Pit-mediated Endocytosis of the Type I Transforming Growth Factor-β (TGF-β) Receptor Depends on a Di-leucine Family Signal and Is Not Required for Signaling

Shapira

Gross

Ehrlich

et al. 2012

Journal of Biological Chemistry

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Transforming Growth Factor β Depletion Is the Primary Determinant of Smad Signaling Kinetics

Cited by 59 publications

References 60 publications

Controlled Delivery of Transforming Growth Factor β1 by Self-Assembling Peptide Hydrogels Induces Chondrogenesis of Bone Marrow Stromal Cells and Modulates Smad2/3 Signaling

Controlled Delivery of Transforming Growth Factor β1 by Self-Assembling Peptide Hydrogels Induces Chondrogenesis of Bone Marrow Stromal Cells and Modulates Smad2/3 Signaling

The regulation of TGFβ signal transduction

Coated Pit-mediated Endocytosis of the Type I Transforming Growth Factor-β (TGF-β) Receptor Depends on a Di-leucine Family Signal and Is Not Required for Signaling

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