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FLASH GENE

Symbol

ALK

contributors: mct/shn - updated : 14-11-2013

HGNC name	anaplastic lymphoma receptor tyrosine kinase
HGNC id	427

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	ALCL ALK-positive anaplastic large-cell lymphoma IMT inflammatory myofibroblastic tumor NBL2 neuroblastoma
Location	2p23.2      Physical location : 29.415.640 - 30.144.432
Synonym name	anaplastic lymphoma kinase (Ki-1)
	CD246 antigen
	ALK tyrosine kinase receptor
	TRK-fused gene-anaplastic lymphoma kinase fusion protein
	mutant anaplastic lymphoma kinase
Synonym symbol(s)	CD246, TFG/ALK, Ki-1, NBLST3
EC.number	2.7.10.1, 2.7.1.112

DNA

TYPE	functioning gene
STRUCTURE	728.80 kb     29 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence

Binding site

MAPPING

cloned

Y

linked

N

status

confirmed

Map	pter - D2S392 - D2S170 - ALK - D2S2383 - D2S375 - cen

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004304 29 - 6222 NP_004295 176.3 1620 - 2008 18923524

EXPRESSION

Type

widely

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 intestine small intestine         mouth tongue     moderately Nervous brain         Reproductive female system ovary     predominantly   male system testis       Respiratory respiratory tract larynx     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous central

cell lineage
cell lines
fluid/secretion	blood

at STAGE

Text	essentially and transiently expressed during development of the central and peripheral nervous system

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	two MAM domain
	one tyrosine kinase catalytic domain
	one LDL receptor class A domain
	nine phosphotyrosine

conjugated

GlycoP

mono polymer

homomer , dimer

HOMOLOGY

interspecies	ortholog to Alk, Rattus norvegicus
	ortholog to Alk, Mus musculus
	ortholog to alk, Danio rerio
	ortholog to ALK, pan troglodytes

intraspecies

homolog to LTK

Homologene

FAMILY	TYR protein kinases family
	insulin receptor subfamily

CATEGORY

protooncogene , receptor membrane

SUBCELLULAR LOCALIZATION	plasma membrane
text	single-pass type I membrane protein

basic FUNCTION	acting as an orphan receptor with a tyrosine-protein kinase activity
	involved in the normal development and function of the nervous system
	involved in activation of RAP1GDS1 that may contribute to cell proliferation and oncogenesis of neuroblastoma driven by gain-of-function mutant ALK receptors
	critical player in neuroblastoma development

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

development

text	important role in brain development

PATHWAY

metabolism

signaling

signal transduction

a component	N-glycosylated
	homodimer, when bound to ligand

INTERACTION

DNA

RNA

small molecule	nucleotide,
	ATP
	zinc could constitute an endogenous ligand of ALK in vertebrates
	interacting with PHOX2B (PHOX2B drives ALK gene transcription by directly binding its promoter, which therefore represents a novel PHOX2B target)

protein	CD30
	Pleiotrophin, PTN
	Jak3
	Midkine, MK
	ShcC
	NIPA
	Grb2, SOCS1, SOCS5, IRS4, Rho-GTPase-activating protein, RAB35, MAP kinase 1, MEK kinase 1,4 and 5, PKC, MLCK, EphA1, ephrinB, JNK kinase 2, cyclin G-associated kinase, meprin, PTPK, protein phosphatase 2 subunit, Hsp60 precursor, PLCitalic gamma1, Jak2, Jak3, Stat3, and IRS, lamin B1RAD17 homolog
	ALK stimulates initiation of transcription of the MYCN gene

cell & other

REGULATION

activated by	zinc (activation is dependent of ALK tyrosine kinase activity and dimerization of the receptor but is independent of Src family kinase activity)
	ShcC

Phosphorylated by

PTN/RPTPbeta/zeta signaling pathway

ASSOCIATED DISORDERS

corresponding disease(s)

IMT , ALCL , NBL2

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral fusion translocation     fused with SEC31L1, in a translocation t(2;4)(p23;q21), in an intraabdominal inflammatory myofibroblastic tumor tumoral   translocation     translocation t(2;5)(p23;q35),(see NPM1) in anaplastic nodal non Hodgkin lymphoma and B cell lymphoma tumoral   inversion     inv(2)(p23;q35)in anaplastic large-cell lymphoma tumoral fusion       with EML4 in non-small-cell lung cancer tumoral germinal mutation       in most hereditary neuroblastomas tumoral somatic mutation     gain of function activating mutations can be somatically acquired in neuroblastoma tumoral       gain of function in neuroblastoma

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target	represent a very attractive therapeutic target in this disease that is still frequently fatal with current treatments (ALK-specific kinase inhibitors might improve its clinical outcome)
	System Type Disorder Pubmed cancer lung   ALK inhibitors may provide a means to control NSCLC in the latter population of patients cancer     identification of the downstream effector pathways controlled by ALK should pave the way for the rational design of ALK-inhibition therapies for the treatment of a subset of human cancers that harbor ALK aberrations cancer brain glioma/neuroblstoma germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for the neuroblastoma, lethal paediatric malignancy cancer     inhibition of ALK kinase activity results in anti-tumoural efficacy

ANIMAL & CELL MODELS

	Forced expression of wild-type ALK and Neuroblastoma-related constitutively active ALK mutants in cultures of proliferating immature sympathetic neurons results in a strong proliferation increase, whereas Alk knockdown and pharmacological inhibition of Alk activity decrease proliferation
	in vivo inhibition of Alk signaling by virus-mediated shRNA knockdown of Alk and Midkine leads to strongly reduced sympathetic neuron proliferation