The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

RIPK2  -  receptor-interacting serine-threonine...

Homo sapiens

Synonyms: CARD-containing IL-1 beta ICE-kinase, CARD-containing interleukin-1 beta-converting enzyme-associated kinase, CARD3, CARDIAK, CCK, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of RIPK2

  • RICK activates a NF-kappaB-dependent anti-human cytomegalovirus response [1].
  • Associated with disease progression, we detect elevation of the caspase-1 activator Rip2 and reduction of the caspase-1 inhibitor Cop [2].
  • For detection of pancreatic cancer, enzyme and bicarbonate outputs in response to CCK are more accurate than pancreatic CEA or bicarbonate outputs in response to secretin [3].
  • These data suggest that a CCK-like peptide is an endogenous modulator of the stomatogastric ganglion of P. interruptus [4].
  • Rick Tarleton and Lei Zhang here consider an alternative view that the primary cause of chronic Chagas disease is the failure of the host to clear the infection, resulting in infection-induced, immune-mediated tissue damage [5].

Psychiatry related information on RIPK2


High impact information on RIPK2

  • Of the many factors that influence food intake, there is strong evidence that opioid and CCK peptides, which stimulate feeding and elicit satiety, respectively, are important components that may act in concert to regulate energy balance [10].
  • However, GTP gamma S binding induced by CCK-8 and vasoactive intestinal polypeptide and the binding capacity of CCK receptors were not different between AGD and pigment stones [11].
  • The cellular kinase activity of RICK, a known signal transducer of inflammatory responses, was already inhibited by submicromolar concentrations of SB 203580 in intact cells [12].
  • We provide multiple lines of data showing that Nod1-dependent apoptosis is a caspase 8-mediated event and that apoptosis requires RIP2 [13].
  • These results demonstrate that RICK functions in innate immunity by mediating Nod1 and Nod2 signaling but not TLR-mediated immune responses [14].

Chemical compound and disease context of RIPK2

  • Treatment of Parkinson's disease with proglumide, a CCK antagonist [15].
  • Secretin significantly (P<0.005-P<0.05) increased volume and bicarbonate output and CCK significantly (P<0.01) increased the output of bilirubin, pancreatic enzymes, bicarbonate and volume, both during normoglycemia and hyperglycemia [16].
  • The recognition and treatment of exercise-induced asthma (EIA) have made significant progress since 1972 when United States swimmer, Rick Demont had his Olympic gold medal award rescinded because of traces of ephedrine were detected in his urine [17].

Biological context of RIPK2

  • These results indicate that adaptor proteins like RIP2 can provide a bifunctional switch for cell survival or cell death decisions mediated by the p75 neurotrophin receptor [18].
  • Interestingly, this region shares no significant sequence homology to the death domain of RIP, the caspase-recruiting domain (CARD) of RIP2 [6][7][8] or any other apoptosis-inducing domain [19].
  • RIP2 activates AP-1 and serum response element regulated expression by inducing the activation of the Elk1 transcription factor [20].
  • Equilibrium and kinetic folding of an alpha-helical Greek key protein domain: caspase recruitment domain (CARD) of RICK [21].
  • In summary, our results indicate that S176 is a regulatory autophosphorylation site for RIP2 and that S176 phosphorylation can be used to monitor the activation state of RIP2 [22].

Anatomical context of RIPK2

  • RIP2, an adaptor protein with a serine threonine kinase and a caspase recruitment domain (CARD), is highly expressed in dissociated Schwann cells and displays an endogenous association with p75 [18].
  • It is demonstrated here that forced expression of RICK in either a kinase active or inactive form activates nuclear factor (NF)-kappaB by means of its intermediate domain and potently blocks HCMV replication in human fibroblasts [1].
  • Receptor-interacting protein 2 (RIP2) is a serine-threonine kinase that mediates signaling for many receptors of the innate and adaptive immune systems [22].
  • CARD tricks: controlling the interactions of CARD6 with RICK and microtubules [23].
  • Consistent with a role for caspase-1 as a scaffold for RIP2, caspase-1 knockout macrophages were suppressed in their ability to activate NF-kappaB, and septic caspase-1 knockout animals produced less IL-6, a functional marker of NF-kappaB activity [24].

Associations of RIPK2 with chemical compounds

  • Here, we have identified a RIP-like kinase, termed CARDIAK (for CARD-containing interleukin (IL)-1 beta converting enzyme (ICE) associated kinase), which contains a serine/threonine kinase domain and a carboxy-terminal CARD [25].
  • One of the known molecular mechanisms underlying pro-caspase-1 processing and activation involves binding of the caspase-1 prodomain to a caspase recruitment domain (CARD)-containing serine/threonine kinase known as RIP2/CARDIAK/RICK [26].
  • RIP2 is a serine-threonine kinase associated with the tumor necrosis factor (TNF) receptor complex and is implicated in the activation of NF-kappaB and cell death in mammalian cells [20].
  • Mutation of S176 to alanine not only abolishes autophosphorylation of RIP2 but also significantly decreases its catalytic activity [22].
  • Knocking down endogenous Rip2/Cop respectively results in reduced/increased sensitivity to neurotoxic stimuli [2].

Physical interactions of RIPK2

  • Nod2 interacted with the serine-threonine kinase RICK via a homophilic CARD-CARD interaction [27].

Enzymatic interactions of RIPK2


Regulatory relationships of RIPK2

  • Overexpression of CARDIAK induced the activation of both NF-kappa B and Jun N-terminal kinase (JNK) [25].
  • Kinase-defective point and deletion variants of RIP2 also significantly blocked the activation of ERK2 by TNFalpha but not epidermal growth factor [20].
  • RIP2 in turn is activated through its interaction with Ras-activated Raf1 [20].
  • Nod2, acting in a reciprocal manner, inhibited TAK1-induced NF-kappaB activation in RICK-deficient embryonic fibroblasts [28].
  • ASC directs NF-kappaB activation by regulating receptor interacting protein-2 (RIP2) caspase-1 interactions [24].

Other interactions of RIPK2

  • Overexpression of TRIP6 potentiates RIP2-mediated NF-kappaB activation in a dose-dependent manner [29].
  • The identification of Nod2 defines a subfamily of Apaf-1-like proteins that function through RICK to activate a NF-kappaB signaling pathway [27].
  • An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways [30].
  • Unlike COP/Pseudo-ICE and procaspase-1, INCA does not interact with RIP2 and does not induce NF-kappaB activation [31].
  • H. pylori infection greatly enhanced MyD88 and TRAF6 complex formation in a cag-dependent manner, but did not enhance Nod1 and receptor-interacting protein 2 complex formation [32].

Analytical, diagnostic and therapeutic context of RIPK2

  • The cross-reactivities of the CCK antisera with several peptides were determined using either a radioimmunoassay or an immunoblot assay; the antisera recognized peptides homologous to CCK but did not cross-react significantly with several unrelated peptides [4].
  • Fat-meal--or CCK-stimulated ultrasonography and quantitative hepatobiliary scintigraphy offer reliable and noninvasive screening methods to evaluate patients with suspected sphincter of Oddi dysfunction [33].
  • Cholecystokinin-like immunoreactivity (CCK-LI) in 0.9 kg human brain was extracted by 2% trifluoroacetic acid at 4 degrees C. Sephadex G50 gel filtration of crude extract revealed one main molecular form of CCK, detected by a carboxy-terminal antibody (5135), that eluted in the position of CCK8 [34].
  • High performance liquid chromatography (HPLC) identified the C-terminal octapeptide of CCK (CCK-8) as the predominant molecular form of CCK within the owl monkey hypothalamus [35].
  • Sphincter of Oddi manometry. Paradoxical response to secretin but not to CCK in alcoholic patients with no pancreatic disease [36].


  1. RICK activates a NF-kappaB-dependent anti-human cytomegalovirus response. Eickhoff, J., Hanke, M., Stein-Gerlach, M., Kiang, T.P., Herzberger, K., Habenberger, P., Müller, S., Klebl, B., Marschall, M., Stamminger, T., Cotten, M. J. Biol. Chem. (2004) [Pubmed]
  2. Dysregulation of receptor interacting protein-2 and caspase recruitment domain only protein mediates aberrant caspase-1 activation in Huntington's disease. Wang, X., Wang, H., Figueroa, B.E., Zhang, W.H., Huo, C., Guan, Y., Zhang, Y., Bruey, J.M., Reed, J.C., Friedlander, R.M. J. Neurosci. (2005) [Pubmed]
  3. Prospective evaluation of the pancreatic secretion of immunoreactive carcinoembryonic antigen, enzyme, and bicarbonate in patients suspected of having pancreatic cancer. DiMagno, E.P., Malagelada, J.R., Moertel, C.G., Go, V.L. Gastroenterology (1977) [Pubmed]
  4. Cholecystokinin-like peptide is a modulator of a crustacean central pattern generator. Turrigiano, G.G., Selverston, A.I. J. Neurosci. (1989) [Pubmed]
  5. Chagas disease etiology: autoimmunity or parasite persistence? Tarleton, R.L., Zhang, L. Parasitol. Today (Regul. Ed.) (1999) [Pubmed]
  6. Effect of oral CCK-1 agonist GI181771X on fasting and postprandial gastric functions in healthy volunteers. Castillo, E.J., Delgado-Aros, S., Camilleri, M., Burton, D., Stephens, D., O'Connor-Semmes, R., Walker, A., Shachoy-Clark, A., Zinsmeister, A.R. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  7. A polymorphism in the 3' untranslated region of the CCK gene is associated with anorexia nervosa in Dutch patients. de Krom, M., Hendriks, J., Hillebrand, J., van Elburg, A., Adan, R. Psychiatr. Genet. (2006) [Pubmed]
  8. Effects of diurnal phase and pimozide on cholecystokinin-elicited hypoactivity in the hamster. Schnur, P., Espinoza, M., Flores, R. Pharmacol. Biochem. Behav. (1992) [Pubmed]
  9. Cholecystokinin as a target for neuropsychiatric drugs. Bourin, M. Drug News Perspect. (1998) [Pubmed]
  10. Role of cholecystokinin and opioid peptides in control of food intake. Baile, C.A., McLaughlin, C.L., Della-Fera, M.A. Physiol. Rev. (1986) [Pubmed]
  11. Gallbladder muscle dysfunction in patients with chronic acalculous disease. Amaral, J., Xiao, Z.L., Chen, Q., Yu, P., Biancani, P., Behar, J. Gastroenterology (2001) [Pubmed]
  12. An efficient proteomics method to identify the cellular targets of protein kinase inhibitors. Godl, K., Wissing, J., Kurtenbach, A., Habenberger, P., Blencke, S., Gutbrod, H., Salassidis, K., Stein-Gerlach, M., Missio, A., Cotten, M., Daub, H. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  13. Regulation of Nod1-mediated signaling pathways. da Silva Correia, J., Miranda, Y., Leonard, N., Hsu, J., Ulevitch, R.J. Cell Death Differ. (2007) [Pubmed]
  14. 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]
  15. Treatment of Parkinson's disease with proglumide, a CCK antagonist. Piolti, R., Appollonio, I., Cocco, E., Ferrarese, C., Frattola, L., Rovati, L., Panerai, A.E. Neurology (1991) [Pubmed]
  16. Effect of acute hyperglycemia on basal, secretin and secretin + cholecystokinin stimulated exocrine pancreatic secretion in humans. Lam, W.F., Masclee, A.A., Souverijn, J.H., Lamers, C.B. Life Sci. (1999) [Pubmed]
  17. What is the current status of management of the patient with exercise-induced asthma? Kobayashi, R.H., Mellion, M.B., Kobayashi, A.L. The Nebraska medical journal. (1994) [Pubmed]
  18. A prosurvival function for the p75 receptor death domain mediated via the caspase recruitment domain receptor-interacting protein 2. Khursigara, G., Bertin, J., Yano, H., Moffett, H., DiStefano, P.S., Chao, M.V. J. Neurosci. (2001) [Pubmed]
  19. Identification of RIP3, a RIP-like kinase that activates apoptosis and NFkappaB. Yu, P.W., Huang, B.C., Shen, M., Quast, J., Chan, E., Xu, X., Nolan, G.P., Payan, D.G., Luo, Y. Curr. Biol. (1999) [Pubmed]
  20. RIP2 is a Raf1-activated mitogen-activated protein kinase kinase. Navas, T.A., Baldwin, D.T., Stewart, T.A. J. Biol. Chem. (1999) [Pubmed]
  21. Equilibrium and kinetic folding of an alpha-helical Greek key protein domain: caspase recruitment domain (CARD) of RICK. Chen, Y.R., Clark, A.C. Biochemistry (2003) [Pubmed]
  22. Identification of a regulatory autophosphorylation site in the serine-threonine kinase RIP2. Dorsch, M., Wang, A., Cheng, H., Lu, C., Bielecki, A., Charron, K., Clauser, K., Ren, H., Polakiewicz, R.D., Parsons, T., Li, P., Ocain, T., Xu, Y. Cell. Signal. (2006) [Pubmed]
  23. CARD tricks: controlling the interactions of CARD6 with RICK and microtubules. Dufner, A., Mak, T.W. Cell Cycle (2006) [Pubmed]
  24. ASC directs NF-kappaB activation by regulating receptor interacting protein-2 (RIP2) caspase-1 interactions. Sarkar, A., Duncan, M., Hart, J., Hertlein, E., Guttridge, D.C., Wewers, M.D. J. Immunol. (2006) [Pubmed]
  25. Identification of CARDIAK, a RIP-like kinase that associates with caspase-1. Thome, M., Hofmann, K., Burns, K., Martinon, F., Bodmer, J.L., Mattmann, C., Tschopp, J. Curr. Biol. (1998) [Pubmed]
  26. Cop, a caspase recruitment domain-containing protein and inhibitor of caspase-1 activation processing. Lee, S.H., Stehlik, C., Reed, J.C. J. Biol. Chem. (2001) [Pubmed]
  27. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. Ogura, Y., Inohara, N., Benito, A., Chen, F.F., Yamaoka, S., Nunez, G. J. Biol. Chem. (2001) [Pubmed]
  28. Reciprocal cross-talk between Nod2 and TAK1 signaling pathways. Chen, C.M., Gong, Y., Zhang, M., Chen, J.J. J. Biol. Chem. (2004) [Pubmed]
  29. TRIP6 is a RIP2-associated common signaling component of multiple NF-kappaB activation pathways. Li, L., Bin, L.H., Li, F., Liu, Y., Chen, D., Zhai, Z., Shu, H.B. J. Cell. Sci. (2005) [Pubmed]
  30. An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways. Inohara, N., Koseki, T., Lin, J., del Peso, L., Lucas, P.C., Chen, F.F., Ogura, Y., Núñez, G. J. Biol. Chem. (2000) [Pubmed]
  31. INCA, a novel human caspase recruitment domain protein that inhibits interleukin-1beta generation. Lamkanfi, M., Denecker, G., Kalai, M., D'hondt, K., Meeus, A., Declercq, W., Saelens, X., Vandenabeele, P. J. Biol. Chem. (2004) [Pubmed]
  32. MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells. Hirata, Y., Ohmae, T., Shibata, W., Maeda, S., Ogura, K., Yoshida, H., Kawabe, T., Omata, M. J. Immunol. (2006) [Pubmed]
  33. The pathophysiology, evaluation and management of motility disorders of the biliary tract. Summers, R.W., Johlin, F.C. Gastroenterol. Clin. North Am. (1989) [Pubmed]
  34. Isolation and characterization of biologically active and inactive cholecystokinin-octapeptides from human brain. Reeve, J.R., Eysselein, V.E., Walsh, J.H., Sankaran, H., Deveney, C.W., Tourtellotte, W.W., Miller, C., Shively, J.E. Peptides (1984) [Pubmed]
  35. Neuronal cholecystokinin-like immunoreactivity is postprandially released from primate hypothalamus. Schick, R.R., Reilly, W.M., Roddy, D.R., Yaksh, T.L., Go, V.L. Brain Res. (1987) [Pubmed]
  36. Sphincter of Oddi manometry. Paradoxical response to secretin but not to CCK in alcoholic patients with no pancreatic disease. Laugier, R., Gerolami, R., Renou, C. Int. J. Pancreatol. (1998) [Pubmed]
WikiGenes - Universities