Cripto Binds Transforming Growth Factor β (TGF-β) and Inhibits TGF-β Signaling

Gray, Peter C.; Shani, Gidi; Aung, Kevin; Kelber, Jonathan A.; Vale, Wylie

doi:10.1128/mcb.01168-06

Cited by 91 publications

(81 citation statements)

References 58 publications

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“…These data represent the first demonstration that endogenously expressed Cripto inhibits activin signaling and confirm our previous demonstration that endogenous Cripto blocks signaling by TGF-β1 (Gray et al, 2006). Knockdown of Cripto and GRP78 together affected the signaling of these TGF-β ligands to a greater extent than knockdown of either protein alone indicating Cripto and GRP78 function cooperatively.…”

Section: Discussionsupporting

confidence: 89%

“…This Cripto co-receptor function is essential during embryogenesis (Strizzi et al, 2005) and it has also been implicated in promoting tumor growth since Nodal plays a key role in promoting tumorigenicity of human melanoma and breast cancer cells (Postovit et al, 2008; Topczewska et al, 2006). In contrast to its role as a Nodal co-receptor, Cripto inhibits activin signaling (Adkins et al, 2003; Gray et al, 2003; Kelber et al, 2008) and cytostatic TGF-β1 effects (Gray et al, 2006; Shani et al, 2008; Shukla et al, 2008). …”

Section: Introductionmentioning

confidence: 99%

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Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways

et al. 2009

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways

et al. 2009

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“…Cripto is one such modulator that affects the signaling of several TGF-␤ ligands that activate the Smad2/3 pathway. These include Nodal (13), GDF1 (32), GDF3 (33), activin-A (20), activin-B (21), and TGF-␤1 (34). Interestingly, although Cripto functions as an obligatory co-receptor for Nodal, GDF1, and GDF3, it antagonizes signaling by activin-A, activin-B, and TGF-␤1.…”

Section: Discussionmentioning

confidence: 99%

Cripto Is a Noncompetitive Activin Antagonist That Forms Analogous Signaling Complexes with Activin and Nodal

Kelber

Shani

Booker

et al. 2008

Journal of Biological Chemistry

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Cripto plays critical roles during embryogenesis and has been implicated in promoting the growth and spread of tumors. Cripto is required for signaling by certain transforming growth factor-␤ superfamily members, such as Nodal, but also antagonizes others, such as activin. The opposing effects of Cripto on Nodal and activin signaling seem contradictory, however, because these closely related ligands utilize the same type I (ALK4) and type II (ActRII/IIB) receptors. Here, we have addressed this apparent paradox by demonstrating that Cripto forms analogous receptor complexes with Nodal and activin and functions as a noncompetitive activin antagonist. Our results show that activin-A and Nodal elicit similar maximal signaling responses in the presence of Cripto that are substantially lower than that of activin-A in the absence of Cripto. In addition, we provide biochemical evidence for complexes containing activin-A, Cripto, and both receptor types and show that the assembly of such complexes is competitively inhibited by Nodal. We further demonstrate that Nodal and activin-A share the same binding site on ActRII and that ALK4 has distinct and separable binding sites for activin-A and Cripto. Finally, we show that ALK4 mutants with disrupted activin-A binding retain Cripto binding and prevent the effects of Cripto on both activin-A and Nodal signaling. Together, our data indicate that Cripto facilitates Nodal signaling and inhibits activin signaling by forming receptor complexes with these ligands that are structurally and functionally similar.

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“…Activin is however antagonized by another secreted molecule, called Follistatin. There is also evidence that Cripto can inhibit signalling from Activin, TGF-b and Myostatin, which have in common to signal via Smad2/3 without requiring an EGF-CFC co-receptor to interact with their receptor complex [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Activin/Nodal signalling before implantation: setting the stage for embryo patterning

Papanayotou

Collignon

2014

Phil. Trans. R. Soc. B

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Activins and Nodal are members of the transforming growth factor beta (TGF-b) family of growth factors. Their Smad2/3-dependent signalling pathway is well known for its implication in the patterning of the embryo after implantation. Although this pathway is active early on at preimplantation stages, embryonic phenotypes for loss-of-function mutations of prominent components of the pathway are not detected before implantation. It is only fairly recently that an understanding of the role of the Activin/Nodal signalling pathway at these stages has started to emerge, notably from studies detailing how it controls the expression of target genes in embryonic stem cells. We review here what is currently known of the TGF-b-related ligands that determine the activity of Activin/Nodal signalling at preimplantation stages, and recent advances in the elucidation of the Smad2/3-dependent mechanisms underlying developmental progression.

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Cripto Binds Transforming Growth Factor β (TGF-β) and Inhibits TGF-β Signaling

Cited by 91 publications

References 58 publications

Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways

Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways

Cripto Is a Noncompetitive Activin Antagonist That Forms Analogous Signaling Complexes with Activin and Nodal

Activin/Nodal signalling before implantation: setting the stage for embryo patterning

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