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Biochemical evidence for the autophosphorylation and transphosphorylation of transforming growth factor beta receptor
1Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
Abstract:
Transforming growth factor beta (TGF-beta) signals through a receptor complex containing the type I (TGF-beta RI) and type II (TGF-beta RII) receptors. We describe here biochemical studies on early events in the TGF-beta signaling pathways. TGF-beta RII is highly phosphorylated when expressed alone in COS-1 cells; its autophosphorylation occurs via an intramolecular (cis) mechanism that is independent of ligand binding. TGF-beta RI is also highly phosphorylated when expressed alone in COS-1 cells. Both wild-type TGF-beta RI and a kinase-deficient mutant thereof are transphosphorylated by the coexpressed TGF-beta RII kinase in a ligand-independent fashion in these cells. We propose that the association of TGF-beta RI and TGF-beta RII, induced by ligand binding or over-expression, leads to transphosphorylation of the TGF-beta RI by the TGF-beta RII kinase. This represents a mechanism of activation of receptors distinct from that of tyrosine kinase receptors and may apply to other serine/threonine kinase receptors.
Insights
Transforming growth factor beta (TGF-beta) signaling involves receptor complex activation. TGF-beta RII kinase transphosphorylates TGF-beta RI, a key step in TGF-beta pathway activation.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Biochemistry
Background:
- Transforming growth factor beta (TGF-beta) is a crucial signaling molecule.
- TGF-beta exerts its effects through a receptor complex.
- This complex includes type I (TGF-beta RI) and type II (TGF-beta RII) receptors.
Purpose of the Study:
- To investigate the early biochemical events in TGF-beta signaling pathways.
- To elucidate the roles of TGF-beta RI and TGF-beta RII in receptor activation.
Main Methods:
- Biochemical studies using COS-1 cells.
- Analysis of receptor phosphorylation (autophosphorylation and transphosphorylation).
- Expression of wild-type and mutant TGF-beta RI with TGF-beta RII.
Main Results:
- TGF-beta RII undergoes ligand-independent intramolecular autophosphorylation.
- TGF-beta RI is also phosphorylated when expressed alone.
- Coexpressed TGF-beta RII kinase transphosphorylates both wild-type and kinase-deficient TGF-beta RI in a ligand-independent manner.
Conclusions:
- Ligand binding or overexpression induces TGF-beta RI and TGF-beta RII association.
- This association leads to TGF-beta RI transphosphorylation by TGF-beta RII kinase.
- This activation mechanism differs from tyrosine kinase receptors and may apply to other serine/threonine kinase receptors.