Phosphorylation of Ser165 in TGF-beta type I receptor modulates TGF-beta1-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 (TbetaR-I) and type II receptor (TbetaR-II). We investigated the in vivo phosphorylation sites in TbetaR-I and TbetaR-II after complex formation. Phosphorylation of TbetaR-II was observed at residues in the C-terminus (Ser549 and Ser551) and at residues in the juxtamembrane domain (Ser223, Ser226 and Ser227). TGF-beta1 induced in vivo phosphorylation of serine and threonine residues in the juxtamembrane domain of TbetaR-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 TbetaR-I kinase. We show here that phosphorylation of TbetaR-I at Ser165 is involved in modulation of TGF-beta1 signaling. Mutations of Ser165 in TbetaR-I led to an increase in TGF-beta1-mediated growth inhibition and extracellular matrix formation, but, in contrast, to decreased TGF-beta1-induced apoptosis. A transcriptional activation signal was not affected. Mutations of Ser165 changed the phosphorylation pattern of TbetaR-I. These observations suggest that TGF-beta receptor signaling specificity is modulated by phosphorylation of Ser165 of TbetaR-I.
Souchelnytskyi
S
S
Ludwig Institute for Cancer Research, Uppsala, Sweden.
ten Dijke
P
P
Miyazono
K
K
Heldin
C H
CH
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010449:Peptide Mapping; D010748:Phosphopeptides / Q000032:analysis / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000032:analysis / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D010748:Phosphopeptides; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D010768:Phosphoserine; D012694:Serine