Regulation of TGF-β signalling by N-acetylgalactosaminyltransferase-like 1
2008
The TGF-β superfamily of secreted signalling molecules plays a pivotal
role in the regulation of early embryogenesis, organogenesis and adult tissue
homeostasis. Here we report the identification of Xenopus
N-acetylgalactosaminyltransferase-like 1 (xGalntl-1) as a novel important
regulator of TGF-β signalling. N-acetylgalactosaminyltransferases mediate
the first step of mucin-type glycosylation, adding N-acetylgalactose to serine
or threonine side chains. xGalntl-1 is expressed in the anterior mesoderm and
neural crest territory at neurula stage, and in the anterior neural crest,
notochord and the mediolateral spinal cord at tailbud stage. Inhibition of
endogenous xGalntl-1 protein synthesis, using specific morpholino oligomers,
interfered with the formation of anterior neural crest, anterior notochord and
the spinal cord. Xenopus and mammalian Galntl-1 inhibited Activin as
well as BMP signalling in the early Xenopus embryo and in human HEK
293T cells. Gain- and loss-of-function experiments showed that xGalntl-1
interferes with the activity of the common TGF-β type II receptor
ActR-IIB in vivo. In addition, our biochemical data demonstrated that
xGalntl-1 specifically interferes with the binding of ActR-IIB to Activin- and
BMP-specific type I receptors. This inhibitory activity of xGalntl-1 was
dependent on mucin-type glycosylation, as it was sensitive to the chemical
inhibitor benzyl-GalNAc. These studies reveal an important role of a
N-acetylgalactosaminyltransferase in the regulation of TGF-β signalling.
This novel regulatory mechanism is evolutionarily conserved and, thus, might
provide a new paradigm for the regulation of TGF-β signalling in
vertebrates.
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