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FLASH GENE

Symbol

RIPK1

contributors: mct/shn - updated : 01-11-2012

HGNC name	receptor (TNFRSF)-interacting serine-threonine kinase 1
HGNC id	10019

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	6p25.2      Physical location : 3.077.057 - 3.115.419
Synonym name	receptor interacting protein
	death domain kinase
	RIP1 kinase
	cell death protein RIP
Synonym symbol(s)	FLJ39204, RIP, RIP1
EC.number	2.7.11.1

DNA

TYPE	functioning gene
STRUCTURE	38.42 kb     10 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

Map	pter - D6S1600 - D6S344 - RIPK1 - D6S1617 - D6S1617 - cen

Physical map

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003804 10 - 3864 NP_003795 - 671 - 2007 17235653

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive esophagus       highly   intestine small intestine       Nervous brain         Reproductive male system testis       Urinary bladder       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective bone     highly

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a N terminal region with homology to protein kinases, and a Ser/Thr kinase domains (KDs)
	an intermediate domain of RIPK1 harbors an anti-apoptotic function, with a RHIM domain
	a C terminal region containing a DEATH domain, and a unique homotypic interaction motif at the C terminus of both RIPK1 and RIPK3 that is required for their association , and also for recruitment to the TNF receptor signaling complex

conjugated

PhosphoP

HOMOLOGY

interspecies	ortholog to Ripk1, Mus musculus
	ortholog to Ripk1, Rattus norvegicus
	ortholog to RIPK1, Pan troglodytes

Homologene

FAMILY	protein kinase superfamily
	TKL Ser/Thr protein kinase family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus
text	present both in the cytoplasm and in the nucleus

basic FUNCTION	dual-function molecule that can be either prosurvival or prodeath depending on its ubiquitination state, and this serves as an NF-kappaB-independent cell-death switch early in TNF signaling
	playing an important role for DNA damage-induced, TP53-independent cell death
	one of the critical components involved in mediating DNA damage-induced, TP53-independent cell death
	one of the major components of the tumor necrosis factor receptor 1 complex and plays an essential role in tumor necrosis factor-mediated nuclear factor kappaB activation (
	plays a critical role in tumor necrosis factor-alpha (TNF)-induced IkappaB kinase (IKK) activation and subsequent activation of transcription factor NF-kappaB
	inhibiting the expression of the epidermal growth factor receptor (EGFR)
	crucial modulator of epidermal differentiation, and important and unique functions in keratinocytes of normal and wounded skin
	specifically recruited to the TNFalpha receptor in the activation of necroptosis
	critical mediator of inflammation and stress-induced NF-kappaB activation, regulates the expression of the epidermal growth factor receptor (EGFR)
	downregulates EGFR expression by interfering with the function of Sp1, which is a key activator of EGFR transcription
	required for death receptor agonists to activate necrosis
	RIPK1 and RIPK3 are key signaling molecules in necrosis and are regulated by caspases and ubiquitination
	required for CD40 ligand-induced caspase-8 activation and tumor cell killing
	RIPK1 and caspase-8 were recruited to the DDX58 complex after viral infection and served antagonistic regulatory roles
	regulates embryogenesis and lymphocyte responses (
	a IKBKG- and RIPK1-based switch mechanism involving TNF-TNFR1 feedforward signaling that mediates ATM-induced cytokine secretion and caspase activation selectively in the context of severe DNA damage
	is a central kinase in TNFR1 signaling participating in NFKB activation, necroptosis, and apoptosis
	functions as a platform mediating survival signals and as an active kinase during necroptosis and apoptosis in the presence of Smac mimetics
	RIPK1, RIPK3 are central players in TNF-induced programmed necrosis
	key switch of cell fate regulation

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

interacting with IKBKG and modulatory NF-kappa B activation and apoptosis

a component

RIPK1 and RIPK3 form an amyloid structure through their RHIMs and that this heterodimeric amyloid structure is a functional signaling complex that mediates programmed necrosis

INTERACTION

DNA

RNA

small molecule	nucleotide,
	ATP

protein	Fas/APO-1 (CD95) (
	TNFRSF1A-associated via death domain, TRADD (
	FADD/MORT1 (
	Death receptor 4, DR4 and Death receptor 5, DR5 (
	TNFRSF1A
	aPKC-binding protein, p62 (
	heat shock protein 90, Hsp90 (
	NEMO (IKKgamma) (
	epidermal growth factor receptor, EGFR (
	IKBKG and modulatory NF6kappa B activation and apoptosis
	RIPK3
	zinc finger protein inhibiting NF-kappa B (
	Focal adhesion kinase, FAK (
	RNF216 (E3 ubiquitin-protein ligase to RIPK1 and Hsp90 and RNF216 cooperatively maintain the homeostasis of RIPK1
	cylindromatosis (turban tumor syndrome), CYLD (
	CSNK1A1
	TAK1 kinase (
	ZBP1 recruits RIPK1 and RIPK3 through RIP homotypic interaction motifs to activate NF-kappaB
	ubiquitin specific peptidase 21, USP21
	links the immunoregulatory CD40 receptor to apoptotic signaling in carcinomas
	RIPK1
	CD40 (
	interacting with ATM (in the context of excessive DNA damage, ATM employs IKBKG and RIPK1 through autocrine TNF signaling to switch on cytokine production and caspase activation)
	PGAM5 is a kinase substrate of RIPK1/RIPK3
	necroptosis depends on the kinases RIPK1 and RIPK3, which interact through their RHIM domains to form the necrosome

cell & other

REGULATION

Other	regulated by TRADD
	negatively regulated by RNF11 (

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   in glomerulus and tubule of class III and IV lupus nephritis

Susceptibility

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	RIP-deficient mice appear normal at birth but fail to thrive, displaying extensive apoptosis in both the lymphoid and adipose tissue and dying at 1-3 days of age (
	RIP1 deficiency allowed normal embryogenesis of Fadd(-/-) mice and the developmental defect of Rip1(-/-) lymphocytes was partially corrected by FADD deletion (
	Fadd(-/-)Rip1(-/-) double-knockout T cells are resistant to death induced by Fas or TNF-&
	945; and show reduced NF-&
	954;B activity (