Cooperative binding of transforming growth factor (TGF)-β2 to the types I and II TGF-β receptors

Abstract

TGF-β1 binds with high affinity (K(D) = 25-50 pM) directly to the TGF-β type II receptor serine-threonine kinase (Tβ-RII) in the absence of expression of the TGF-β type I or III receptors (Tβ-RI and Tβ-RIII). The serine-threonine kinase Tβ-RI is essential for TGF-β1 signaling but not for binding to Tβ-RII. TGF-β2, in contrast, does not bind directly to Tβ-RII, although coexpression of Tβ-RIII does allow binding and cross-linking of TGF-β2 to Tβ-RII. Here we show that in transfected COS cells binding and cross-linking of 125I-TGF-β2 to Tβ-RI or Tβ-RII requires expression of both receptors. In cells transfected with the c-myc-tagged human Tβ-RII cDNA, only low amounts of 125I-TGF-β2 cross-linked to Tβ-RI and Tβ-RII were detected even with high concentrations (700 pM) of ligand. Cotransfection of the influenza-hemagglutinin-tagged human Tβ-RI cDNA dramatically increased the binding of TGF-β2 to Tβ-RII; the concentration of 125I-TGF-β2 required for half-maximal binding and cross-linking to Tβ-RI and Tβ-RII was ~40 pM. Coimmunoprecipitation studies showed that the high affinity receptor for TGF-β2 is composed of a hetero-oligomer of Tβ- RI and Tβ-RII. Thus TGF-β1 and -β2 bind to TGF-β receptors in different ways; TGF-β1 binds directly to Tβ-RII, while binding of TGF-β2 to Tβ-RII requires coexpression of Tβ-RI or Tβ-RIII.