Abstract
Transforming growth factor-beta (TGF-beta) transduces signals through its type I and type II receptors. Both receptor types have previously been shown to interact in a heteromeric complex in the presence of TGF-beta. We have now characterized these interactions between both receptor types using a combination of yeast two-hybrid interaction assays and coimmunoprecipitation analyses. Our results indicate a direct association between the cytoplasmic domains of the two receptor types. Mutation analysis of these cytoplasmic domains reveals that this direct interaction requires kinase activity and, thus, depends on phosphorylation, probably via a transphosphorylation mechanism. Furthermore, the two receptor types already have an inherent affinity for each other in the absence of TGF-beta, and the heteromeric complex can be detected in coimmunoprecipitations under these conditions. Taken together, our results reveal a novel mechanism of receptor complex formation, whereby two different cytoplasmic domains directly associate with each other. This interaction may play a major role in activation of serine/threonine kinase receptors.
Highlights
Transforming growth factor {3 (TGF-{3)1 belongs to a family of multifunctional proteins which regulate cell proliferation, differentiation, and formation of the extracellular matrix [1, 2]
Direct Interaction of the Cytoplasmic Domains of the Type I and Type II Receptors-Since the type I and type II receptors have the ability to interact in a heteromeric complex, we evaluated the involvement of different receptor domains in this interaction
We examined whether the cytoplasmic domains of the two receptor types undergo a direct physical interaction
Summary
Transforming growth factor {3 (TGF-{3) belongs to a family of multifunctional proteins which regulate cell proliferation, differentiation, and formation of the extracellular matrix [1, 2]. The type II receptor is a transmembrane serine/threonine kinase, the cytoplasmic domain of which can be autophosphorylated when expressed in Escherichia coli [12] This receptor is constitutively autophosphorylated when transfected into mammalian cells [13], which is consistent with its homodimeric complex formation [14,15,16]. The type I TGF-{3 receptor was identified using chemical cross-linking techniques as a 53-kDa glycoprotein [17], and several closely related type I TGF-{3 receptors have been cloned [18,19,20,21,22] They contain an intracellular serine/threonine kinase domain, but do not bind ligand unless coexpressed with the type II receptor. The phosphorylation-dependent interaction of two cytoplasmic domains represents a novel mechanism for dimerization and/or oligomerization of receptors, which may be required for signaling ofTGF-{3-related factors through their transmembrane serine/threonine kinase receptors
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