→ TRAF6|ubi|hm2|active@Cytosol References
PMID:18758450
The ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in TGFBR1.
The TGFBR1???TRAF6 interaction is required for TGFB-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1???p38/JNK pathway
TGFB specifically activates TAK1 (MAP3K7) through interaction of TGFBRI with TRAF6.
The kinase activity of TGFBRI is not required for activation of TAK1 and p38.
Model in which TGFB - induced activation of TAK1 is initiated by ligand-induced oligomerization of TGFBreceptors. This in turn cause dimerization of TRAF6, followed by auto-ubiquitylation and activation.
This possibility is consistent with the observation that artifical dimerization of TRAF6 causes its auto-ubiquitylation.
Activated TRAF6 then causes Lys 63-linked ubiquitylation and activation of TAK1 (MAP3K7). TAK1 may be further activated by juxtaposition-induced autophosphorylation.
The recruitment of TAK1 may be facilitated by Smad7, which has been shown to have an adaptor function in the pathway
PMID:18922473
TRAF6 is specifically required for the Smad-independent activation of JNK and p38.
The carboxyl TRAF homology domain physically interacts with TGFB receptors.
TGFB induces K63-linked ubiquitination of TRAF6 and promotes association between TRAF6 and TAK1 (MAP3K7).
TGFB activates JNK and p38 through a mechanism similar to that operating in the interleukin1B/Toll- like receptor pathway.