RIPK1 is phosphorylated

Stable Identifier
Reaction [transition]
Homo sapiens
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RIPK1 interaction with RIPK3 further potentiates their kinase activation through autophosphorylation and/or cross?phosphorylation (Cho YS et al. 2009). The kinase function of RIPK1 and RIPK3 is thought to stabilize RIPK1:RIPK3 association within the pronectrotic complex.

Reconstitution of RIPK1-deficient human Jurkat cells with mutated kinase?inactive RIPK1 or RIPK1 lacking the N-terminal serine/threonine kinase domain did not trigger FASL?induced necrotic cell death (Holler N et al. 2000). Similarly, mutations in the kinase domain and RIP homotypic interaction motif (RHIM) of RIPK1 also abolished the RIPK1-mediated rescue of TNF/zVAD-fmk-induced regulated necrosis in RIPK1-deficient Jurkat cells (Cho YS et al. 2009). Furthermore, the results of structural and mutagenesis studies using necrostatins, which inhibit RIPK1 kinase activity by targeting the kinase domain, revealed that the N-terminal kinase domain of RIPK1 is required for propagating the pronecrotic signal (Degterev A et al. 2008; Cho YS et al. 2009; Xie T et al. 2013). Mass spectroscopy showed that RIPK1 is phosphorylated within the kinase domain at multiple serine residues, such as Ser14/15, Ser20, Ser161 and Ser166, suggesting that the phosphorylation might regulate RIPK1 kinase activity (Degterev A et al. 2008). However, site-directed mutagenesis revealed that alanine substitution of individual serine residues in the kinase domain of RIP1 had little effects on RIP1 kinase activity and TNF-induced programmed necrosis (McQuade T et al. 2013). At the same time, Ser89 was identified as an inhibitory phospho-acceptor site that may reduce RIP1 kinase activity to limit RIP1-dependent programmed necrosis (McQuade T et al. 2013). Thus, the biological role of phosphorylation on the serine residues in the kinase domain of RIPK1 remain to be further characterized.

RIPK3 might also regulate RIPK1 phosphorylation in mammalian cells. For instance, RIPK3 was shown to directly phosphorylate RIPK1 when kinase-dead RIPK1 and RIPK3 were co-expressed in human embryonic kidney HEK293 cells, immunoprecipitated, and subjected to an in vitro kinase assay (Sun X et al. 2001; Cho et al. 2009). Importantly, mutation within RHIM motif of RIPK3 abrogated RIPK1 phosphorylation by RIPK3, suggesting that RIPK1 phosphorylation by RIPK3 is dependent on the formation of the RIPK1:RIPK3 complex (Sun X et al. 2001).?

Literature References
PubMed ID Title Journal Year
19524513 Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation

Cho, YS, Challa, S, Moquin, D, Genga, R, Ray, TD, Guildford, M, Chan, FK

Cell 2009
24059293 Positive and negative phosphorylation regulates RIP1- and RIP3-induced programmed necrosis

McQuade, T, Cho, Y, Chan, FK

Biochem. J. 2013
Participant Of
Catalyst Activity
Catalyst Activity
protein serine/threonine kinase activity of RIPK1:RIPK3 [cytosol]
Physical Entity
Orthologous Events