Disease relevance of RIPK3

• In this study, we showed that a truncated form of RIP3 (tRIP3) containing only the unique C-terminal region (aa 224-518) induced significant apoptosis in human hepatocellular carcinoma cells QGY-7703 [1].
• Importantly, real-time PCR analysis reveals that the ratio of RIP3 gamma to RIP3 is significantly increased in colon and lung cancers relative to their matched normal tissues, indicating that RIP3 gamma might be a major splice form associated with tumorigenesis [2].

High impact information on RIPK3

• In this study, we have mapped a minimal region of RIP3 sufficient for apoptosis induction to a fragment of 31 amino acids in length [3].
• Nucleocytoplasmic shuttling of receptor-interacting protein 3 (RIP3): identification of novel nuclear export and import signals in RIP3 [3].
• This interaction is a prerequisite for RIP3-mediated phosphorylation of RIP and subsequent attenuation of TNF-induced NF-kappaB activation [4].
• RIP3 binds RIP through this unique C-terminal segment to inhibit RIP- and TNF receptor-1-mediated NF-kappaB activation [4].
• RIP2 and RIP3 are related kinases that share extensive sequence homology with the kinase domain of RIP [4].

Biological context of RIPK3

• These experiments further characterize RIP3-mediated apoptosis and NF-kappaB activation [5].
• Furthermore, point mutations of RIP3 at amino acids conserved among death domains, abrogated its apoptotic activity [5].
• The rip3 gene was localized by fluorescent in situ hybridization to human chromosome 14q11.2, a region frequently altered in several types of neoplasia [5].
• Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3 [4].
• We demonstrate that cAMP stimulation of guanylyl cyclase, which is required for chemotaxis, is reduced approximately 60% in rip3 null cells [6].

Anatomical context of RIPK3

• RIP3 was localized by immunofluorescence to the mitochondrion and may play a key role in the mitochondrial disruptions often associated with apoptosis [5].
• Northern blots indicate that rip3 mRNA displays a restricted pattern of expression including regions of the adult central nervous system [5].
• A double-knockout mutant (rip3/aleA null cells) exhibits a further reduction in receptor activation of guanylyl cyclase, and these cells display almost no cell polarization or movement in cAMP gradients [6].
• Using normal and abnormal human fetal hearts and cultured normal human fetal cardiomyocytes, we show that congenital cardiovascular malformations are associated with the overexpression of hRIP3, and evidence is found for a certain association between overexpression of hRIP3 and homocysteine-induced congenital cardiovascular malformations [7].

Associations of RIPK3 with chemical compounds

• RIP3 binds RIP through its unique C-terminal segment and by virtue of this interaction is recruited to the tumor necrosis factor (TNF) receptor-1 signaling complex [8].
• RIP3 (receptor-interacting protein 3) is a serine/threonine kinase that promotes apoptosis in various cell types [1].
• Surv-D53A was shown to markedly sensitize apoptosis induced by TRAIL, doxorubicin, and RIP3 [9].
• Homocysteine, hRIP3 and congenital cardiovascular malformations [7].

Regulatory relationships of RIPK3

• In contrast, the RIP3 dominant negative (RIP3-DN) was found unable to block FADD-induced apoptosis [1].

Other interactions of RIPK3

• RIP3-mediated apoptosis was inhibited by Bcl-2, Bcl-x(L), dominant-negative FADD, as well as the general caspase inhibitor Z-VAD [5].
• RIP3, however, attenuates both RIP and TNF receptor-1-induced NF-kappaB activation [8].
• As with RIP and RIP2, the kinase domain of RIP3 was not required for either NFkappaB activation or apoptosis induction [10].

Analytical, diagnostic and therapeutic context of RIPK3

• Further dissection of caspase involvement in RIP3-induced apoptosis indicated inhibition by the more specific inhibitors Z-DEVD (caspase-3, -6, -7, -8, and -10) and Z-VDVAD (caspase-2) [5].

References