RIPK2

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RIPK2

A gene on chromosome 8q21 that encodes a serine/threonine/tyrosine kinase which is intimately involved in modulating innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerise, and recruit RIPK2 through CARD-CARD domains. Once recruited, RIPK2 autophosphorylates and undergoes “Lys-63”-linked polyubiquitination by E3 ubiquitin ligases BIRC2 and BIRC3. The polyubiquitinated protein then recruits MAP3K7/TAK1 to IKBKG/NEMO, induces “Lys-63”-linked polyubiquitination of IKBKG/NEMO and activates IKBKB/IKKB.

In turn, NF-kappaB is released from NF-kappaB inhibitors and translocates to the nucleus, where it activates transcription of myriad genes involved in immune response, growth control or anti-apoptosis. It also plays a role during engagement of the T-cell receptor in promoting BCL10 phosphorylation and subsequent NF-kappaB activation.
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RIP2 ubiquitination is regulated by a number of E3 ligases including various cellular inhibitor of apoptosis proteins (cIAPs) and TNF-receptor associated factors (TRAFs).
Pellino 3 and ITCH are two additional E3 ligases contributing to RIP2 polyubiquitination.
The positive effect of polyubiquitinating E3-ligases on RIP2 activation is counterbalanced by the negative effect of deubiquitinating enzymes that remove poly ubiquitin chains from target molecules.
As for the molecular mechanisms leading to IFN-[beta] production via NOD1 activation, detailed over-expression and knock-down studies revealed that NOD1 binding to its ligand leads to activation of RIP2 followed by the physical interaction between RIP2 and various TRAFs, such as TRAF2, TRAF5, and TRAF6 that then play a role in RIP2-mediated NF-[kappa]B activation.
provided evidence that endosomal co-localization of NOD1 and RIP2 following bacterial OMV uptake leads to autophagy and inflammatory responses in gastric epithelial cells.
pylori induces autophagosome formation in a NOD1 and RIP2-dependent manner and that OMV and their contained PGN then co-localize with both NOD1 and RIP2 in early endosomes.
They thus concluded that the unique ability of NOD1-activated RIP2 to interact with TRAF3 leads to down-regulation of NF-[kappa]B support of Cdx2 expression.
Thus, whereas stimulation of CCKR by low dose cerulein induces protein kinase C (PKC) and TAK1 activation as in previous studies, (112) the level of such activation by low dose cerulein alone is not sufficient to induce activation of NF-[kappa]B; likewise, NOD1 activation of RIP2 also is not sufficient to induce activation of NF-[kappa]B.
2014) The immune receptor NOD1 and kinase RIP2 interact with bacterial peptidoglycan on early endosomes to promote autophagy and inflammatory signaling.
2008) RIP2 contributes to Nod signaling but is not essential for T cell proliferation, T helper differentiation or TLR responses.
2013) Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis.
2009) ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways.