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FLASH GENE

Symbol

MAP3K12

contributors: mct/npt - updated : 24-08-2012

HGNC name	mitogen-activated protein kinase kinase kinase 12
HGNC id	6851

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	12q13.13      Physical location : 53.874.276 - 53.893.444
Synonym name	dual leucine zipper kinase DLK
	protein kinase MUK
	zipper protein kinase
Synonym symbol(s)	ZPK, DLK, MUK, ZPKP1
EC.number	2.7.11.25

DNA

TYPE	functioning gene
SPECIAL FEATURE	arranged in tandem
STRUCTURE	19.17 kb     15 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	cytosine-phosphate-guanine/HTF
	Binding site   transcription factor
text structure	core promoter region is TATA-less, but contains several potential transcription factor-binding motifs such as a GC-box, positively regulated by SP3

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001193511 14 - 3640 NP_001180440 - 892 - 2005 15695824 NM_006301 15 - 3541 NP_006292 93 859 - 2005 15695824

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 Respiratory lung       highly   respiratory tract larynx     highly Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective bone       Muscular striatum skeletal     Nervous central

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron Skin/Tegument keratinocyte

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal

Text

brain

PROTEIN

PHYSICAL PROPERTIES		basic
STRUCTURE

motifs/domains	N terminal kinase catalytic domain, hybrid between those of serine/threonine and tyrosine protein kinases
	a double leucine zipper domain
	a large C terminal glycine and proline rich region

conjugated

HemoP

mono polymer

dimer

HOMOLOGY

interspecies

homolog to murine Map3k12

Homologene

FAMILY	MAP (mitogen activated protein) kinase family
	Mixed lineage kinase family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
text	phosphorylated and dephosphorylated in cytosol and dephosphorylated only when membrane-associated

basic FUNCTION	serine/threonine protein kinase contributing in the developing brain to cytodifferentiation, apoptotic elimination, and migration
	acting in the epidermis to promote the terminal differentiation of keratinocytes
	acting as a signaling molecule implicated in the regulation of keratinocyte terminal differentiation and cornification
	plays a significant role in the coordinated regulation of radial migration and axon projection by modulating JNK activity
	potential role in PDGF signaling
	potentially involved in regenerative responses of mammalian dorsal root ganglion neurons to axonal injury through activation of c-JUN
	plays a significant role in the coordinated regulation of radial migration and axon projection by modulating JNK activity
	key regulator of development, cell differentiation and apoptosis
	critical role in naturally occurring programmed cell death of motoneurons
	selectively regulates the JNK-based stress response pathway to mediate axon degeneration and neuronal apoptosis without influencing other aspects of JNK signaling
	participates in cell proliferation and/or survival, at least in part, by modulating the expression of cell cycle regulatory proteins
	appears to be important for proper cell proliferation and/or cell survival
	cell cycle-regulated protein whose depletion by RNA interference causes proliferation arrest concomitantly with senescence
	essential component of the neuronal response to axon damage, broadly regulating the transcriptional response to axonal injury
	is required for both the proapoptotic and proregenerative responses that occur after optic nerve lesion through broad regulation of injury-induced alterations in gene expression

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

signaling

signal transduction

	JNK cascade
	MAP3K12-JNK pathway facilitates axon formation in neocortical neurons via stage-specific regulation of microtubule stability
	MAP3K12-ERK signaling pathway may act as a regulator of the interaction that occurs between HSPB1 and the cytoskeleton during the formation of the cornified cell envelope, a process conferring to the skin its crucial barrier function (PMIDS:

a component

INTERACTION

DNA

RNA

small molecule	metal binding,
	Mg2+

protein	interacting with the GTP bound form of RAC and CDC42, regulators of JNK pathway
	induces activation of c-Jun N-terminal kinase (JNK), a molecule that regulates morphogenesis in various organisms
	its expression, is sufficient by itself to induce HSPB1 phosphorylation, cell periphery localization, and redistribution to the insoluble protein fraction (cytoskeleton) in poorly differentiated keratinocytes (PMIDS:
	novel transcriptional target of PPARG with functional PPARG-binding sites in its promoter

cell & other

REGULATION

activated by

phosphorylation

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   MAP3K12 depletion interrupts progression of the cell cycle from the G1 to S phase

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neuromuscular spinal muscular atrophy   could become a strategic therapeutic target in motor neuron diseases in which aberrant activation of the apoptogenic cascade is involved

ANIMAL & CELL MODELS

Map3k12-null mice displayed reduced apoptosis in multiple neuronal populations during development, demonstrating that prodegenerative Map3k12 signaling is required in vivo