COOPERATIVE BINDING OF TRANSFORMING GROWTH-FACTOR (TGF)-BETA-2 TO THE TYPE-I AND TYPE-II TGF-BETA RECEPTORS

TGF-beta 1 binds with high affinity (K-D = 25-50 pM) directly to the TGF-beta type II receptor serine-threonine kinase (T beta-RII) in the absence of expression of the TGF-beta type I or III receptors (T beta-RI and T beta-RIII). The serine-threonine kinase T beta-RI is essential for TGF-beta 1 signaling but not for binding to T beta-RII. TGF-beta 2, in contrast, does not bind directly to T beta-RII, although coexpression of T beta-RIII does allow binding and cross-linking of TGF-beta 2 to T beta-RII. Here we show that in transfected COS cells binding and cross-linking of I-125-TGF-beta 2 to T beta-RI or T beta-RII requires expression of both receptors. In cells transfected with the c-myc-tagged human T beta-RII cDNA, only low amounts of I-125-TGF-beta 2 cross-linked to T beta-RI and T beta-RII were detected even with high concentrations (700 pM) of ligand. Cotransfection of the influenza-hemagglutinin-tagged human T beta-RI cDNA dramatically increased the binding of TGF-beta 2 to T beta-RII; the concentration of I-125-TGF-beta 2 required for half-maximal binding and cross-linking to T beta-RI and T beta-RII was similar to 40 pM. Coimmunoprecipitation studies showed that the high affinity receptor for TGF-beta 2 is composed of a hetero-oligomer of T beta-RI and T beta-RII. Thus TGF-beta 1 and -beta 2 bind to TGF-beta receptors in different ways; TGB-beta 1 binds directly to T beta-RII, while binding of TGF-beta 2 to T beta-RII requires coexpression of T beta-RI T beta-RIII.