Disease relevance of Ripk2

• Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death [1].
• Inhibition of p38 MAP kinase- and RICK/NF-kappaB-signaling suppresses inflammatory bowel disease [2].
• Here we show that Rip2-deficient mice exhibit a profoundly decreased ability to defend against infection by the intracellular pathogen Listeria monocytogenes [3].
• In vivo, Rip2-deficient mice were resistant to the lethal effects of LPS-induced endotoxic shock [3].
• This tissue-specific determinant(s) was detected in the RIP-1 and RIP-2 human pancreatic adenocarcinomas carried as xenografts in athymic nude mice [4].

Psychiatry related information on Ripk2

• These data imply that while CCK induces relatively protracted and exaggerated behavioral disturbances, mu/delta opioid-receptor activation may block CCK-induced behavioral sensitization and change the course of psychopathology [5].

High impact information on Ripk2

• Moreover, cytokine production in Rip2-deficient cells was reduced on stimulation of TLRs with lipopolysaccharide, peptidoglycan and double-stranded RNA, but not with bacterial DNA, indicating that Rip2 is downstream of TLR2/3/4 but not TLR9 [6].
• RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems [6].
• RESULTS: CCK-induced intracellular Ca(2+) mobilization, Ca(2+) influx, trypsinogen, and NF-kappa B activation were all diminished in pancreatic acini isolated from p110 gamma(-/-) mice [7].
• CARD6 associates with microtubules and interacts with receptor-interacting protein (RIP)-like interacting caspase-like apoptosis regulatory protein kinase (RICK), a CARD-containing member of the RIP family of protein kinases [8].
• A mutant deficient in kinase activity, however, had effects similar to wild-type RIP2, indicating that phosphorylation was not essential to the function of RIP2 [9].

Chemical compound and disease context of Ripk2

• Dominant-negative RhoN19, Clostridium botulinum C3 exotoxin, which inhibits Rho, and dominant-negative RacN17 all partially blocked CCK-induced acinar morphological changes and actin redistribution [10].

Biological context of Ripk2

• Unlike RIP and RIP2, mRIP3 mRNA is expressed in a subset of adult tissues and is thus likely to be a tissue-specific regulator of apoptosis and NF-kappaB activity [11].
• These results demonstrate that RICK functions in innate immunity by mediating Nod1 and Nod2 signaling but not TLR-mediated immune responses [12].
• In conclusion, activation and possibly upregulation of CN may participate in regulation of pancreatic growth by CCK in mice [13].
• Using a subtractive cDNA library hybridization approach, we found that receptor interacting protein 2 (RIP2), a tumor necrosis factor receptor 1 (TNFR-1)-associated factor, is a novel early-acting gene that decreases markedly in expression during myogenic differentiation [9].
• RICK is composed of an N-terminal serine-threonine kinase catalytic domain and a C-terminal region containing a caspase-recruitment domain [14].

Anatomical context of Ripk2

• Rip2 is therefore a signal transducer and integrator of signals for both the innate and adaptive immune systems [6].
• Furthermore, deficiency in Bcl10-dependent NF-kappaB activation could be rescued in Rip2-/- embryonic fibroblasts by exogenous wild-type Rip2 but not a kinase-dead mutant [15].
• We show here that macrophages and mice lacking RICK are defective in their responses to Nod1 and Nod2 agonists but exhibit unimpaired responses to synthetic and highly purified TLR agonists [12].
• Importantly, we show that astrocytes express Rip2 kinase, an essential downstream effector molecule for NOD-mediated cell responses, and demonstrate that this expression is upregulated after bacterial challenge [16].
• In addition, we have shown that osteoblasts express Rip2 kinase, a critical downstream effector molecule for Nod signaling [17].

Associations of Ripk2 with chemical compounds

• Herein we demonstrate that Rip2, a caspase recruitment domain (CARD)-containing serine/threonine kinase, plays an important role in this cascade and is required for optimal TCR signaling and NF-kappaB activation [15].
• Thus, the inhibitory effect of SB203580 on NF-kappaB activation is to a large extent mediated by RICK inhibition [18].
• The increase in plasma CCK induced by camostat was not blocked by CsA or FK506 [13].
• Significantly, expression of a RICK mutant in which the lysine of the putative ATP-binding site at position 38 was replaced by a methionine functioned as an inhibitor of CD95-mediated apoptosis [14].
• Receptor interacting protein-2 (RIP2) contains an N-terminal domain with homology to Ser/Thr kinases and a C-terminal caspase activation and recruitment domain (CARD), a homophilic interaction motif that mediates the recruitment of caspase death proteases [19].

Other interactions of Ripk2

• Here we show the impact of ASC-, Ipaf- or RIP2-deficiency on inflammasome function [20].
• RIP, RIP2, and mRIP3 contain an N-terminal kinase domain that share 30 to 40% homology [11].

Analytical, diagnostic and therapeutic context of Ripk2

• We therefore tested the effect of two different CN inhibitors, cyclosporine A (CsA) and FK506, on mouse pancreatic growth induced by oral administration of the synthetic protease inhibitor camostat, a known stimulator of endogenous CCK release [13].

References