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Gene Review

Ripk2  -  receptor (TNFRSF)-interacting serine...

Mus musculus

Synonyms: 2210420D18Rik, CARD3, CARDIAK, CCK, D4Bwg0615e, ...
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Disease relevance of Ripk2


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].


  1. Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death. Zhang, W.H., Wang, X., Narayanan, M., Zhang, Y., Huo, C., Reed, J.C., Friedlander, R.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  2. Inhibition of p38 MAP kinase- and RICK/NF-kappaB-signaling suppresses inflammatory bowel disease. Hollenbach, E., Neumann, M., Vieth, M., Roessner, A., Malfertheiner, P., Naumann, M. FASEB J. (2004) [Pubmed]
  3. Involvement of receptor-interacting protein 2 in innate and adaptive immune responses. Chin, A.I., Dempsey, P.W., Bruhn, K., Miller, J.F., Xu, Y., Cheng, G. Nature (2002) [Pubmed]
  4. Identification of a human pancreatic duct tissue-specific antigen. Gold, D.V., Hollingsworth, P., Kremer, T., Nelson, D. Cancer Res. (1983) [Pubmed]
  5. Central D-Ala2-Met5-enkephalinamide mu/delta-opioid receptor activation blocks behavioral sensitization to cholecystokinin in CD-1 mice. Hebb, A.L., Zacharko, R.M. Brain Res. (2003) [Pubmed]
  6. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Kobayashi, K., Inohara, N., Hernandez, L.D., Galán, J.E., Núñez, G., Janeway, C.A., Medzhitov, R., Flavell, R.A. Nature (2002) [Pubmed]
  7. Phosphatidylinositide 3-kinase gamma regulates key pathologic responses to cholecystokinin in pancreatic acinar cells. Gukovsky, I., Cheng, J.H., Nam, K.J., Lee, O.T., Lugea, A., Fischer, L., Penninger, J.M., Pandol, S.J., Gukovskaya, A.S. Gastroenterology (2004) [Pubmed]
  8. Caspase recruitment domain protein 6 is a microtubule-interacting protein that positively modulates NF-kappaB activation. Dufner, A., Pownall, S., Mak, T.W. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  9. RIP2, a checkpoint in myogenic differentiation. Munz, B., Hildt, E., Springer, M.L., Blau, H.M. Mol. Cell. Biol. (2002) [Pubmed]
  10. Rho and Rac promote acinar morphological changes, actin reorganization, and amylase secretion. Bi, Y., Page, S.L., Williams, J.A. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  11. Mouse receptor interacting protein 3 does not contain a caspase-recruiting or a death domain but induces apoptosis and activates NF-kappaB. Pazdernik, N.J., Donner, D.B., Goebl, M.G., Harrington, M.A. Mol. Cell. Biol. (1999) [Pubmed]
  12. RICK/RIP2 Mediates Innate Immune Responses Induced through Nod1 and Nod2 but Not TLRs. Park, J.H., Kim, Y.G., McDonald, C., Kanneganti, T.D., Hasegawa, M., Body-Malapel, M., Inohara, N., Núñez, G. J. Immunol. (2007) [Pubmed]
  13. Calcineurin mediates pancreatic growth in protease inhibitor-treated mice. Tashiro, M., Samuelson, L.C., Liddle, R.A., Williams, J.A. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  14. RICK, a novel protein kinase containing a caspase recruitment domain, interacts with CLARP and regulates CD95-mediated apoptosis. Inohara, N., del Peso, L., Koseki, T., Chen, S., Núñez, G. J. Biol. Chem. (1998) [Pubmed]
  15. Rip2 participates in Bcl10 signaling and T-cell receptor-mediated NF-kappaB activation. Ruefli-Brasse, A.A., Lee, W.P., Hurst, S., Dixit, V.M. J. Biol. Chem. (2004) [Pubmed]
  16. Functional expression of NOD2, a novel pattern recognition receptor for bacterial motifs, in primary murine astrocytes. Sterka, D., Rati, D.M., Marriott, I. Glia (2006) [Pubmed]
  17. Induction of Nod1 and Nod2 intracellular pattern recognition receptors in murine osteoblasts following bacterial challenge. Marriott, I., Rati, D.M., McCall, S.H., Tranguch, S.L. Infect. Immun. (2005) [Pubmed]
  18. Inhibition of RICK/nuclear factor-kappaB and p38 signaling attenuates the inflammatory response in a murine model of Crohn disease. Hollenbach, E., Vieth, M., Roessner, A., Neumann, M., Malfertheiner, P., Naumann, M. J. Biol. Chem. (2005) [Pubmed]
  19. RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase. McCarthy, J.V., Ni, J., Dixit, V.M. J. Biol. Chem. (1998) [Pubmed]
  20. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Mariathasan, S., Newton, K., Monack, D.M., Vucic, D., French, D.M., Lee, W.P., Roose-Girma, M., Erickson, S., Dixit, V.M. Nature (2004) [Pubmed]
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