The type I ALK4 and ALK6 receptors compete for the type II activin receptor to mediate signaling to distinct Smad pathways

Signaling by the transforming growth factor-β superfamily (TGF-β-SF) cytokines is a key regulator of multiple biological processes and diseases. They signal via specific type II and type I receptor complexes, where the type II receptor phosphorylates and activates the type I receptor and elicits signaling. Here we studied the activin type II receptor (ACVR2a) which can function both in activin signaling (with ALK4/7 type I receptors) and in BMP signaling (with ALK1/2/3/6 as type I receptors). Using Patch-FRAP biophysical studies (where one receptor is immobilized at the cell surface by IgG crosslinking, and the lateral diffusion of the second receptor is measured) complemented by signaling studies, we show that ACVR2a forms complexes which are stable on the FRAP timescale (minutes) with various type I receptors (ALK3, ALK4, ALK6). Importantly, ALK4 and ALK6 compete with each other for binding ACVR2a. In U2OS cells, where both BMP9 signaling to Smad1/5/8 and ActA signaling to Smad2/3 are mediated via ACVR2a, the competition between ALK4 and ALK6 is reflected by concomitant inhibition of the respective Smad pathways. We conclude that competition between type I receptors that signal to different Smad pathways for ACVR2a is a novel mechanism for the regulation of activin vs. BMP signaling pathways. This mechanism may have implications for various diseases.