Phosphorylation of Ser165 in TGF-beta type I receptor modulates TGF-beta 1-induced cellular responses

Transforming growth factor-beta (TGF-beta) signals via an oligomeric complex of two serine/threonine kinase receptors denoted TGF-beta type I receptor (T beta R-I) and type II receptor (T beta R-II). We investigated the in vivo phosphorylation sites in T beta R-I and T beta R-II after complex formation. Phosphorylation of T beta R-II was observed at residues in the C-terminus (Ser549 and Ser551) and at residues in the juxtamembrane domain (Ser223, Ser226 and Ser227). TGF-beta 1 induced in vivo phosphorylation of serine and threonine residues in the juxtamembrane domain of T beta R-I in a region rich in glycine, serine and threonine residues (GS domain; Thr185, Thr186, Ser187, Ser189 and Ser191), and more N-terminal of this region (Ser165). Phosphorylation in the GS domain has been shown previously to be involved in activation of the T beta R-I kinase. We show here that phosphorylation of T beta R-I at Ser165 is involved in modulation of TGF-beta 1 signaling. Mutations of Ser165 in T beta R-I led to an increase in TGF-beta 1-mediated growth inhibition and extracellular matrix formation, but, in contrast, to decreased TGF-beta 1-induced apoptosis. A transcriptional activation signal was not affected. Mutations of Ser165 changed the phosphorylation pattern of T beta R-I. These observations suggest that TGF-beta receptor signaling specificity is modulated by phosphorylation of Ser165 of T beta R-I.