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FLASH GENE

Symbol

MAP3K1

contributors: mct/npt/pgu - updated : 15-10-2018

HGNC name	mitogen-activated protein kinase kinase kinase 1
HGNC id	6848

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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 Endocrine thyroid       highly Lymphoid/Immune lymph node       highly Reproductive female system ovary     highly

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal

Text	highly expressed in the posterior of the developing eye and is required for retina development
	highly expressed in the developing eyelid epithelium

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a RING domain within its N-terminal regulatory region
	a SWIM (SWI2/SNF2 and MuDR) domain, proximal to the RING domain, directly associating with the JUN DNA-binding domain, and required for MAP3K1-dependent JUN ubiquitylation
	a kinase catalytic domain, hybrid between those of serine/threonine and tyrosine protein kinases
	a PHD domain Ring-type zinc finger, required for JNK activation and efficient induction of apoptosis by drugs causing cytoskeletal disruption
	a docking site, a stretch of about 20 amino acids immediately on the C-terminal side of the MAPKK catalytic domain

conjugated

PhosphoP

HOMOLOGY

interspecies	homolog to murine Map3k1
	homolog to C.elegans R13d11.7

Homologene

FAMILY	protein kinase superfamily
	STE Ser/Thr protein kinase family
	MAP kinase kinase kinase subfamily

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,cytoplasm,cytoskeleton
text	the cleaved 91kDa form is relocated from a particulate fraction to soluble cytoplasmic fraction

basic FUNCTION	exercizing an antiapoptotic function as activator of C-Jun amino-terminal kinase (JNK) in response to changes in the microtubule cytoskeleton and extra signal-regulated protein kinase (ERK)
	stimulating MADH2 mediated transcriptional activation in endothelial cells
	acting as an E3 ubiquitin-ligase (by its PHD domain) and mediating ubiquitination and degradation of ERK1/2
	involved in apoptosis as caspase-3 substrate and in the induction of apoptosis by genotoxins but not by microtubule altering drugs
	important downstream component in the MAPK cascade that serves to integrate a variety of extracellular signals, and REG3A activity can be modulated through ERK signaling pathways by extracellular signals
	required with TRAF6 by HSPPD2A to activate NF-kappaB and mitogen-activated protein kinases that are critical for the optimal induction of type I interferons
	transmits wound signals, leading to the transcriptional activation of genes involved in extracellular matrix homeostasis, epithelial cell migration, and wound reepithelialization
	involved in the canonical Wnt signalling pathway and positively regulates expression of Wnt target genes
	activates the MAPK JNK and is required for microtubule inhibitor-induced apoptosis in B cells
	novel role for MAP3K1 in which it crosstalks with the cell cycle regulatory pathways in the prevention of retina malformation and degeneration
	integrates developmental signals for eyelid closure
	potential roles of MAP3K1 in differentiation and lineage specification
	both the MAP3K1 PHD and TAB1 are critical for ES-cell differentiation and tumourigenesis
	potential crucial role of MAP3K1 in the development and function of inner ear and hearing
	plays a major role in MAPK signaling, has been implicated in mechanical processes in cells, such as migration

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

importance of the MAP3K1-CNN3 signaling pathway to cell contractility

a component

INTERACTION

DNA

RNA

small molecule	nucleotide,
	ATP

protein	with CEBPB (activation for regulating gene expression)
	binding ceramide
	regulatory kinase for REG3A
	physically interacted with CRTC1 and stimulated its nuclear translocation
	interacting with STK10 (MAP3K1 and STK10 may have opposing roles in regulating the CD28RE/AP1 element of IL2)
	AXIN1 inter-actor in JUN NH(2)-terminal kinase pathway
	DCAF7 required to allow coupling of MAP3K1 to DYRK1 and HIPK2 (DCAF7 is a novel scaffold protein regulating kinase signalling by HIPK2 and MAP3K1)
	forms with JUN, a regulatory axis that orchestrates morphogenesis by integrating two different networks of eyelid closure signals
	MAP3K1 mediates TP53 protein stability in the presence of MDM2 and reduces TP53 ubiquitination, suggesting an interference with MDM2-mediated degradation of TP53 by the ubiquitin-proteasome pathway (26018553)
	BAALC induced cell-cycle progression of leukemia cells by sustaining extracellular signal-regulated kinase (ERK) activity through an interaction with a scaffold protein MAP3K1, which inhibits the interaction between ERK and MAP kinase phosphatase 3 (MKP3/DUSP6)
	COPS6 associates with MAP3K1 and reduces MAP3K1 expression level by facilitating the ubiquitin-mediated degradation of MAP3K1
	MAP3K1 colocalizes with CNN3 at the actin cytoskeleton and phosphorylates it, leading to an increase in the cell-generated traction stress

cell & other

REGULATION

activated by	autophosphorylation
	stress activated

ASSOCIATED DISORDERS

corresponding disease(s)

XYDSDM

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation       mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination tumoral     --low   led to a potent inhibition on the invasion and migration of human pancreatic adenocarcinoma

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer digestive pancreas may be a potential target for development of anti-invasion and metastasis drugs in pancreatic cancer

ANIMAL & CELL MODELS

	Mekk1 knockout mice; Map3k1 within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination
	mice lacking Map3k1 are fertile and exhibit no overt abnormalities of testis development
	Map3K1-deficient mice exhibit increased proliferation and apoptosis, and Muller glial cell overproduction in the developing retinas