RIPK1


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Related to RIPK1: necroptosis, PubMed

RIPK1

A gene on chromosome 6p25.2 that encodes a serine/threonine/tyrosine kinase which transduces inflammatory and cell-death signals (necroptosis), triggered in response to the binding of ligands to death receptors, activation of pathogen recognition receptors (PRRs) and DNA damage. Activation of TNFR1 by TNF-alpha family cytokines recruits TRADD and TRAF2 to the receptor; ubiquitination by TRAF2 enhances communication with downstream signal transducers in the mitogen-activated protein kinase (MAPK) and NF-kappaB pathways, activating genes that encode inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappaB activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 form a necroptosis-inducing complex.
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References in periodicals archive ?
Inhibition of RIPK1 with Nec-1 ameliorated necrotic characters of cardiomyocytes (reduction of cells fracture, etc.) (Figure 2(e)).
To further investigate the role of necroptosis in PA-induced cardiomyocyte hypertrophy, we also used a gene silencing approach to specifically knockdown RIPK1 and RIPK3 expression.
When the ER stress in H9c2 cells was suppressed, we observed that the ER stress markers were downregulated (Figure 3(b)) and the gene expression of RIPK1 and RIPK3 was also decreased compared to PA stimulation group (Figure 3(c)).
After specifically blocking RIPK1 by Nec-1, the increased phosphorylation of AKT (Ser473) and mTOR (Ser2481) induced by PA stimulation was inhibited (Figures 4(b) and 4(c)), suggesting that activation of AKT/mTOR in response to PA in NCMs is RIPK1-dependent.
The major findings are that (1) necroptosis is involved in PA-induced cardiomyocyte hypertrophy; (2) there is a crosstalk between ER stress and necroptosis in PA stimulated hypertrophic cardiomyocytes; and (3) mTOR is identified as one of the molecular bases underlying PA-induced hypertrophy, which might be a downstream signaling molecule of RIPK1.
It is negatively regulated by caspase and is dependent on the kinase activity of RIPK1 and RIPK3.
Nec-1 could inhibit RIPK1 expression, endogenous RIPK1 autophosphorylation, and even the formation of RIPK1-RIPK3 complex [22, 30, 33].
However the mTOR inhibitor rapamycin has no influence on the expression of RIPK1, indicating that RIPK1 might be an upstream signal molecule of PA-induced AKT/mTOR activation.
A recent study has shown that acidosis-induced necroptosis in neurons is dependent on acid-sensing ion channel 1a- (ASIC1a-) mediated RIPK1 phosphorylation [69].
Werner et al., "RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis," Cell Death and Differentiation, vol.
Caption: Figure 4: RIPK1 cleavage at pH 7.4 and 6.7.