Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

RIPK1 (Q13546) - Overview - Molecular Target Synopsis

Protein


RIPK1, Receptor-interacting serine/threonine-protein kinase 1
Enzyme Classification 2.7.11.1
UniProt Q13546

Also Known as RIPK1_HUMAN, RIPK1, RIP, RIP1

Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage (PubMed:11101870, PubMed:17389591, PubMed:19524512, PubMed:19524513). Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor (PubMed:11101870, PubMed:17389591, PubMed:19524512, PubMed:19524513). Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade (PubMed:17389591). Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules (PubMed:15258597). Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death (PubMed:15258597). RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex (PubMed:19524513, PubMed:19524512). Interacts (via RIP homotypic interaction motif) with RIPK3 (via RIP homotypic interaction motif) (PubMed:11734559, PubMed:29883609, PubMed:19524512, PubMed:10358032). Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation of this complex leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase activity (PubMed:22265414). Interacts (via the death domain) with TNFRSF6 (via the death domain) and TRADD (via the death domain) (PubMed:8612133). Is recruited by TRADD to TNFRSF1A in a TNF-dependent process (PubMed:24130170). Binds RNF216, EGFR, IKBKG, TRAF1, TRAF2 and TRAF3 (PubMed:8612133, PubMed:9927690, PubMed:11854271, PubMed:11116146). Interacts with BNLF1 (PubMed:10409763). Interacts with SQSTM1 upon TNF-alpha stimulation (PubMed:10356400). May interact with MAVS/IPS1 (PubMed:16127453). Interacts with ZFAND5 (PubMed:14754897). Interacts with RBCK1 (PubMed:17449468). Interacts with ZBP1 (By similarity). Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4 (PubMed:21931591). Interacts (via kinase domain) with DAB2IP (via Ras-GAP domain); the interaction occurs in a TNF-alpha-dependent manner (PubMed:17389591). Interacts with ARHGEF2 (PubMed:21887730). Interacts (via protein kinase domain) with RFFL; involved in RIPK1 ubiquitination (PubMed:18450452). Interacts with RNF34; involved in RIPK1 ubiquitination (Ref.33). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with PELI1 (PubMed:29883609). Interacts (via Death domain) with CRADD (via Death domain); the interaction is direct (PubMed:9044836).

5ZMZ
4 RESIDUE FRAGMENT OF
AMYLOID CORE OF RIP1
IN THE STRUCTURE OF
AMYLOID CORE OF RIP1
RCSB/PDB
Inspect Structure
See all 3D Structures for RIPK1

Isoforms / Transcripts (Protein Coding)


Protein Length Ensembl Gene Ensembl Transcript Ensembl Protein Uniprot Isoform
671ENSG00000137275ENST00000259808, ENST00000380409ENSP00000259808, ENSP00000369773Q13546-1
625ENSG00000137275ENST00000541791ENSP00000442294Q13546-2

Sub-cellular localization


UniProt: RIPK1 is active in the following subcellular-locations: cell membrane, cytoplasm.
GO terms: RIPK1 is active in the following subcellular-locations: cytosol, death-inducing signaling complex, endosome membrane, membrane raft, mitochondrion, receptor complex, ripoptosome.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project RIPK1 has gain in 1 cell-lines, loss in 2 cell-lines and no signal in 1002 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: MDA_MB_231, HS578T, MALME_3M

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: M059J, NCI-H209, G122

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, NHLF, HSMM

(see details)

RNA Interference


RIPK1 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: SKGT4, ZR7530. (see details)

3D Structures


For RIPK1 there are:
11 structures (25 chains) solved
9 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


RIPK1 has been screened with 162 compounds (376 bioactivities), 54 compounds have bioactivities that show binding affinity of <= 500nM (119 bioactivities). (see details)