Functional Roles for the Cytoplasmic Domain of the Type III Transforming Growth Factor β Receptor in Regulating Transforming Growth Factor β Signaling

Transforming growth factor β (TGF-β) signals through three high affinity cell surface receptors, TGF-β type I, type II, and type III receptors. The type III receptor, also known as betaglycan, binds to the type II receptor and is thought to act solely by “presenting” the TGF-β ligand to the type II receptor. The short cytoplasmic domain of the type III receptor is thought to have no role in TGF-β signaling because deletion of this domain has no effect on association with the type II receptor, or with the presentation role of the type III receptor. Here we demonstrate that the cytoplasmic domains of the type III and type II receptors interact specifically in a manner dependent on the kinase activity of the type II receptor and the ability of the type II receptor to autophosphorylate. This interaction results in the phosphorylation of the cytoplasmic domain of the type III receptor by the type II receptor. The type III receptor with the cytoplasmic domain deleted is able to bind TGF-β, to bind the type II receptor, and to enhance TGF-β binding to the type II receptor but is unable to enhance TGF-β2 signaling, determining that the cytoplasmic domain is essential for some functions of the type III receptor. The type III receptor functions by selectively binding the autophosphorylated type II receptor via its cytoplasmic domain, thus promoting the preferential formation of a complex between the autophosphorylated type II receptor and the type I receptor and then dissociating from this active signaling complex. These studies, for the first time, elucidate important functional roles of the cytoplasmic domain of the type III receptor and demonstrate that these roles are essential for regulating TGF-β signaling. Transforming growth factor β (TGF-β) signals through three high affinity cell surface receptors, TGF-β type I, type II, and type III receptors. The type III receptor, also known as betaglycan, binds to the type II receptor and is thought to act solely by “presenting” the TGF-β ligand to the type II receptor. The short cytoplasmic domain of the type III receptor is thought to have no role in TGF-β signaling because deletion of this domain has no effect on association with the type II receptor, or with the presentation role of the type III receptor. Here we demonstrate that the cytoplasmic domains of the type III and type II receptors interact specifically in a manner dependent on the kinase activity of the type II receptor and the ability of the type II receptor to autophosphorylate. This interaction results in the phosphorylation of the cytoplasmic domain of the type III receptor by the type II receptor. The type III receptor with the cytoplasmic domain deleted is able to bind TGF-β, to bind the type II receptor, and to enhance TGF-β binding to the type II receptor but is unable to enhance TGF-β2 signaling, determining that the cytoplasmic domain is essential for some functions of the type III receptor. The type III receptor functions by selectively binding the autophosphorylated type II receptor via its cytoplasmic domain, thus promoting the preferential formation of a complex between the autophosphorylated type II receptor and the type I receptor and then dissociating from this active signaling complex. These studies, for the first time, elucidate important functional roles of the cytoplasmic domain of the type III receptor and demonstrate that these roles are essential for regulating TGF-β signaling. transforming growth factor β bone morphogenetic protein glutathione S-transferase kinase-dead hemagglutinin Transforming growth factor β (TGF-β)1 is a member of a family of dimeric polypeptide growth factors which, in addition to the TGF-β ligands, includes the bone morphogenetic proteins (BMPs) and the activins (1Massague J. Annu. Rev. Biochem. 1998; 67: 753-791Crossref PubMed Scopus (3975) Google Scholar). TGF-β regulates cellular proliferation and differentiation as well as the processes of embryonic development, wound healing, and angiogenesis in a in TGF-β receptors or signaling have in association with the of and in the of TGF-β ligand have also to and of the and J. PubMed Scopus Google Scholar). TGF-β regulates cellular processes by binding to three high affinity cell surface receptors, the TGF-β type I, type II, and type III receptors. the type III receptor, also known as betaglycan, is the TGF-β receptor and is thought to by binding TGF-β and then to its signaling receptor, the type II receptor. This is important for the TGF-β2 bind the type II receptor The type I and II receptors protein in cytoplasmic domains signaling by of the family of for TGF-β signaling has TGF-β binds to type III receptors, then TGF-β to type II receptors, or to type II receptors by TGF-β, type II receptors and type I receptors, protein kinase The type I receptors or that then bind to The then the in a manner with factors to the of a a of have to this through of type I and type II proteins that TGF-β signaling the receptor as well as and that interact with to TGF-β signaling the J. J. PubMed Google Scholar). also by the formation of receptor that then TGF-β some have that the type I receptor the of TGF-β on the the type II receptor the of TGF-β on the cell PubMed Scopus Google J. PubMed Scopus Google Scholar). signaling, and signaling through protein kinase and cellular signaling has J. PubMed Scopus Google J. PubMed Scopus Google J. PubMed Google J. J. J. PubMed Scopus Google J. Google Scholar). the of TGF-β receptor in TGF-β signaling, we the by the type III receptor and the role of the type III receptor in TGF-β signaling. The type III receptor with the type II receptor or the type I receptor, as well as with the type II and type I receptors that the interaction of the type III receptor with the type II receptor through domains because deletion of the cytoplasmic domain of the type III receptor the ability of these receptors to interact J. J. PubMed Scopus Google Scholar). no functional role for the cytoplasmic domain of the type III receptor has The a role for a and interaction between the cytoplasmic domains of the type II and type III receptors. The protein kinase activity of the type II receptor and of the type II receptor are to essential for this results in the phosphorylation of the cytoplasmic domain of the type III receptor by the type II receptor. The type III receptor with its cytoplasmic domain deleted is able to bind TGF-β, the type II receptor, and enhance TGF-β binding to the type II receptor but is unable to enhance TGF-β2 signaling. The type III receptor functions by selectively binding autophosphorylated type II receptor via its cytoplasmic domain, promoting the formation of a complex between the autophosphorylated type II receptor and the type I receptor, and then dissociating from this active signaling complex. 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PubMed Scopus Google Scholar). of these to that important for kinase and and that important for TGF-β signaling. in or to no effect on the ability of the type II receptor to interact with the cytoplasmic domain of the type III receptor. of to or in with the ability of the type II receptor to interact with the cytoplasmic domain of the type III receptor. the ability of these of the type II receptor to the type III receptor and in the type III receptor in the of the type II receptor or the of the type II receptor, the with and the phosphorylation of the type III receptor and type II receptor by in of the type II receptors with the of the type able to the type III receptor with ability type the and of the type II receptor able to and ability to with ability to interact with the cytoplasmic domain of the type III receptor These results demonstrate that kinase activity of the type II receptor is but for its interaction with the type III receptor and that of the type II receptor is as the cytoplasmic domain of type III receptor selectively with the autophosphorylated of the type II receptor and of the type II receptor is for type II receptor and TGF-β signaling, these results a by this interaction TGF-β signaling. have that the cytoplasmic domain of the type III receptor is essential for formation of a complex between the type II and type III receptors or for the presentation role of the type III receptor, the that the cytoplasmic domain of the type III receptor important role in regulating TGF-β signaling. the role of the cytoplasmic domain of the type III receptor in TGF-β signaling, we the ability of the type III receptor and of the type III receptor the cytoplasmic domain to bind TGF-β, bind the type II receptor, TGF-β to the type II receptor, and TGF-β signaling. 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The of the cytoplasmic domain of the type III receptor on TGF-β signaling of the type III receptor binding TGF-β, with the type II receptor and the TGF-β ligand to the type II receptor. The results with the that the cytoplasmic domain of the type III receptor selectively with and regulates type II receptor. of the TGF-β ligand to the type II receptor, the type III receptor the type II receptor to the type I the of the type III receptor in these is the type III receptor with the type II receptor and the type I receptor, or the type III receptor from the active between the type II receptor and the type I receptor. of these the the effect of the cytoplasmic domain of the type III receptor on the type III receptor, the type II receptor, and the type I receptor the the type II receptor and the type III receptor a complex with and then the type I receptor is to this of the type I receptor to a of the type II receptor and the type III receptor or the type receptor. 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TGF-β binds to the type III receptor TGF-β to the autophosphorylated type II receptor via a interaction of the cytoplasmic domain of with the cytoplasmic domain of autophosphorylated the complex of TGF-β, and and binds the type I receptor and and the cytoplasmic domain of from the active signaling complex of and the active signaling complex or to TGF-β signaling. are by the TGF-β a of through signaling of factors that interact with the TGF-β signaling the type I and type II and and factors that interact with the factors and have These proteins the of the and to the TGF-β (1Massague J. Annu. Rev. Biochem. 1998; 67: 753-791Crossref PubMed Scopus (3975) Google Scholar). for the of are through the cell surface receptors for TGF-β as well as through signaling from these receptors. Here we for essential and role of the type III receptor in TGF-β signaling by a functional interaction of the cytoplasmic domains of the type III receptor with the type II receptor. This interaction is by the ability of cytoplasmic domain of the type II receptor to interact with the cytoplasmic domain of the type III receptor as by the binding of the type III receptor to the and the type II receptor are the for kinase activity of the type II receptor for this the ability of the type II receptor to the cytoplasmic domain of the type III and the of the cytoplasmic domain of the type III receptor for autophosphorylated type II receptor. The of this interaction is by the of of the type III receptor the cytoplasmic domain to a type III receptor TGF-β2 signaling. The of of the type III receptor in signaling the ability of the cytoplasmic domain of the type III receptor to bind type II receptor and the ability of the type III receptor to from the active signaling complex of the type II receptor and the type I receptor. The type III receptor has thought to have a role in TGF-β signaling, to ligand to the signaling type I and type II receptors. this presentation the type III receptor binds TGF-β and then the type II receptor and TGF-β to the type II receptor. The type II receptor is by binding TGF-β and the type I receptor a complex and to signaling The presentation role for the type III receptor by the affinity of the type III receptor for TGF-β for the type III receptor for the type II the of signaling in the short cytoplasmic domain of the type III receptor, and the ability of to to TGF-β in the of type III receptor results have to this of the and cell that the type III receptor, and the receptor, to the type III receptor in the cytoplasmic These to but are to as bind to TGF-β2 by of the type III receptor, essential role for the type III receptor in TGF-β2 signaling J. PubMed Scopus Google Scholar). The type III receptor has also to have essential role in TGF-β signaling, the of TGF-β or on in embryonic PubMed Scopus Google Scholar). the of functional type III receptor on is to to TGF-β Google Scholar). the type III receptor to bind and signaling by TGF-β PubMed Scopus Google Scholar). The results interaction of the cytoplasmic domain of the type III receptor with the type II receptor, the phosphorylation of the type III receptor by the type II receptor, and the essential role of the cytoplasmic domain of the type III receptor in TGF-β signaling that the type III receptor is essential for the of TGF-β, for the TGF-β2 The type III receptor the cytoplasmic domain bind the type II receptor and TGF-β binding to the type II receptor, but this is to enhance signaling. the type III receptor a in in the type III receptor selectively the formation of the active signaling complex between the autophosphorylated type II receptor and the type I receptor. The type III receptor this by selectively binding the type II receptor via its cytoplasmic domain, the interaction of the autophosphorylated type II receptor with the type I receptor, and then dissociating from the signaling complex between the type II receptor and the type I receptor. This the phosphorylation of the type III receptor by the type II receptor as the cytoplasmic domain of the type III receptor is and with the receptor, no has for this deletion of the cytoplasmic domain to have no effect on the ability of the type III receptor to bind TGF-β, to bind the type II receptor, or to enhance TGF-β binding to the type II receptor J. J. PubMed Scopus Google Scholar). we that the type III receptor its cytoplasmic domain bind TGF-β, with the type II receptor, and TGF-β to the type II receptor, its ability to TGF-β2 signaling in a is The the role of the cytoplasmic domain of the type III receptor on in the ability of the type III receptor the cytoplasmic domain to bind the type II receptor and enhance TGF-β binding the ability to enhance TGF-β signaling J. J. PubMed Scopus Google Scholar). The functions to the cytoplasmic domain of the type III receptor, phosphorylation by the type II receptor, specifically with the cytoplasmic domain of the autophosphorylated type II receptor and dissociating the type III receptor from the complex of the type II receptor and the type I receptor, to essential for the role of the type III receptor in TGF-β signaling. phosphorylation of the type III receptor by the type II receptor the by the type III receptor is from the active signaling complex. The role of the cytoplasmic domain is by that the domains of the type II and type III receptors bind TGF-β2 in manner and that the binding of the domain of the type III receptor to TGF-β2 binding of the domain of the type II receptor to and J. The association of the cytoplasmic domain of the type III receptor with the type II receptor or via protein that binds to the autophosphorylated type II receptor the type III receptor cytoplasmic have unable to demonstrate a interaction of the cytoplasmic domain of the type III receptor with the type II receptor in and with the cytoplasmic domain of the type III receptor the type II we have a protein that bind the cytoplasmic domain of the type III receptor. a binds to a I binding in the cytoplasmic domain of the type III receptor. and in the I binding of the type III receptor binding of to the type III receptor, but effect the interaction between the type III receptor and the type II receptor that this protein is protein in this the of the type III receptor and the of to TGF-β, the of the cytoplasmic domain of the type III receptor in TGF-β signaling. The type III receptor as and able to these and with the that the is the type III receptor is with type III receptors. 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