Reactome | RIPK3 binds p-S9-PRKN

RIPK3 binds p-S9-PRKN

Stable Identifier

R-HSA-9793472

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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E3 ubiquitin-protein ligase parkin (PRKN, also known as PARK2), was shown to negatively regulate necroptosis in human and mouse cells through promoting polyubiquitination of receptor-interacting protein 3 (RIPK3) (Lee SB et al. 2019). Endogenous PRKN co-immunoprecipitated with RIPK3, but not RIPK1 or MLKL, in human colorectal adenocarcinoma HT29 cells in response to T/C/Z treatment (TNF-ɑ with cycloheximide and the caspase inhibitor zVAD (Z)) (Lee SB et al. 2019). Mutagenesis analysis revealed that the N-terminal domain of RIPK3 is required for its binding to PRKN. IBR and R2 domains of PRKN were sufficient for the RIPK3:PRKN interaction (Lee SB et al. 2019). AMP-activated protein kinase (AMPK), a sensor of low intracellular ATP levels, was found to phosphorylate PRKN in mouse embryonic fibroblasts (MEF). AMPK phosphorylated mouse PRKN at S9, a highly conserved residue among vertebrates. Further, AMPK suppressed necroptosis and inflammation-related tumorigenesis by regulating PRKN activity in azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model of inflammatory colorectal cancer (Lee SB et al. 2019). The data suggest that AMPK activates PRKN by phosphorylation, which in turn binds RIPK3 to promote RIPK3 polyubiquitination (Lee SB et al. 2019).

This Reactome events shows RIPK3 binding to PRKN. However, enrichment of human RIPK3 from HT29 cells via FLAG-immunoprecipitation for mass spectrometry did not detect PRKN as a RIPK3 interactor (Meng Y et al. 2022), indicating some context specific association that requires further elaboration for complete understanding.

Literature References

PubMed ID	Title	Journal	Year
31358971	The AMPK-Parkin axis negatively regulates necroptosis and tumorigenesis by inhibiting the necrosome Tong, SY, Chung, JO, Lou, Z, Kim, SS, Zhang, JS, Luo, Q, Han, SA, Lee, SB, Choi, SI, Nowsheen, S, Kim, JJ, Fan, Y, Springer, W, Park, SY, Fiesel, FC, Yin, P, Guo, LS, Aziz, A, Aziz, K	Nat Cell Biol	2019