Phosphorylation Shifts TGF-β Receptor Affinity

Abstract

Activation of the transmembrane receptor type I for transforming growth factor-β (TGF-β) requires its phosphorylation by transmembrane receptor type II (TβR-II). Phosphorylation of serine and threonine residues occurs in the conserved juxtamembrane domain of TβR-I called the GS region, but just how multiple phosphorylation activates the receptor to signal to downstream molecules including the transcription factor Smad has not been clear. Huse et al. show that a tetraphosphorylated form of the GS region had increased affinity for Smad2. When not phosphorylated, the GS region bound to the inhibitory immunophilin FKBP12. FKBP12 interaction is known to stabilize a catalytically inactive form of TβR-I. The presence of the nucleotide ATP weakened FKBP12-TβR interaction, suggesting competitive binding. The authors propose that when unphosphorylated, TβR-I assumes a conformation that binds to either FKBP12 or ATP. Phosphorylation of the GS region activates the receptor by eliminating binding of FKBP12 and enhancing affinity for the Smad substrate. M. Huse, T.W. Muir, L. Xu, Y.-G. Chen, J. Kuriyan, J. Massagué, The TGFβ receptor activation process: An inhibitor- to substrate-binding switch. Mol. Cell 8 , 671-682 (2001). [Online Journal]