CD246 ALK (anaplastic lymphoma kinase)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
T Cell
Neural Cell
Endothelial Cell
Brain
Small intestine
Nervous system
Testis
Spinal cord
200 / 200

Expression
CD246 is expressed on a subtype of T cell lymphomas.  Expression is on anaplastic T cell leukemias, the small intestine, testis, brain and CNS but not on normal lymphocytes.  It is detectable on rare scattered neural cells, pericytes and endothelial cells but is absent from other cell types.  CD246 expression occurs principally in perinatal neural cells with high levels in the dienchephhalon midbrain and ventral half of the spinal cord.  Exprssion is also in trigeminal sympathetic and enteric ganglia.  After birth expression decreases but it still detectable in the thalamus, olfactory bulb and mesenchephalon.   CD246 fusion proteins arising from chromosomal translocation are found in ALCLs and in inflammatory myofibroblastic tumor.  Expression has been reported in peripheral nerve sheath tumors  leiomyosarcoma, some neuroblastomas, a few rhabdomyosarcomas and on a rare subtype of B cell lymphoma.

 




Structure
MOLECULAR FAMILY NAME: Belongs to the insulin receptor family.

CD246 is a single-pass type-1 aa glycoprotein.  It contains a 20 aa  putative signal sequence, an 1030 aa extracellular domain which contains 16 potential N-glycosylation sites and 26 cysteine residues which are present with 2 clusters between 425-487 aa and 987-1021 aa which may confer ligand specificity, a 28 aa transmembrane domain and an intracellular cytoplasmic domain which contains a 64 aa juxtamembrane domain, a 254 aa tyrosine kinase domain and a 244 aa carboxyl tail which has several potential SH2 and PTB binding sites.  A juxtamembrane region contains a potential binding site for proteins with SH2 domains that is also found in other membranes of the insulin receptor subfamily and is also shown to mediate the interaction of receptor tyrosine kinases with substrates such as IRS-1.  The tyrosine kinase domain has paired tyrosine amino acids are characteristic of major autophosphorylation sites of the insulin receptor family.  CD246 is a receptor tyrosine kinase with homology to leukocyte tyrosine kinase (LTK) and is a member of the insulin receptor superfamily (INSR).     

The 2:5 chromosomal translocation is frequently associated with anaplastic large cell lymphomas (ALCLs).  The translocation creates a fusion gene consisting of the anaplastic lymphoma kinase (ALK) gene and the nucleophosmin (NPM) gene. The 3' half of ALK, derived from chromosome 2, is fused to the 5' portion of NPM from chromosome 5.  A recent study shows that the product of the NPM-ALK fusion gene is oncogenic.  The deduced amino acid sequences reveal that CD246 is a novel receptor protein-kinase having a putative transmembrane domain and an extracellular domain.  These sequences are absent in the product of the transforming NPM-ALK gene.  CD246 shows the greatest sequence similarity to leukocyte tyrosine kinase (LTK). 

MOLECULAR MASS
Cell Line Unreduced Reduced Comment
Rh30 200 kDa ALK (CD246)
SKNMC, SKNSH neuroblastoma 200 kDa ALK (CD246)
B cell lymphoma 200 kDa ALK (CD246)
SU-DHL-1 80 kDa NPM-ALK
ALCL 95 kDa-105 kDa TPM3-ALK
ALCL 97 kDa TFG-ALK
ALCL 96 kDa ATIC-ALK
ALCL 250 kDa CLTCL-ALK
ALCL 125 kDa MSN-ALK
Myofibroblastic tumor 95 kDa-105 kDa TPM3-ALK
Myofibroblastic tumor 250 kDa CLTC-ALK
Myofibroblastic tumor 161 kDa RanBP2-ALK

ABBREVIATIONS:  NPM=nucleophosim, TPM=tropomyosin, TFG=TRK fused gene, ATIC=s-aminoimidazole-4 carboxamide ribonucleotide formyl-transferase/IMP cyclohydrase, CLTCL=clathrin-like polypeptide chain, MSN=moesin, CLTC=clathrin heavy chain, RanBP2=Ran-binding protein 2. 

POST-TRANSCRIPTIONAL MODIFICATION

CD246 has 6226 bp encoding a protein of 1620 aa with a predicted Mr of 177 kDa.

POST-TRANSLATIONAL MODIFICATION

CD246 is N-glycosylated which occurs during the synthesis of the mature receptor.


Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD246

Pleiotrophin and midkine are putative ligands for CD246.  CD246 has predicited binding sites for P13 kinase, RasGAP, PLC-g, and P13 kinase was studied using NPM-ALK.

Function
The exact function of CD246 is unknown but since CD246 is a receptor tyrosine kinase, it can be assumed that it phosphorylates intracellular molecules leading to the transmission of signals from the cell exterior to the nucleus.  CD246 is thought to play a role in signal transduction via the mitogen-activated protein kinase (MAPK) pathway and is involved in the normal development and function of the nervous system.  There is a possible role in cellular proliferation, neurite differentiation, apoptosis and embryonic neural differentiation.  Knockout mice are phenotypically normal, which indicates CD246 is nonessential at least in mice.  Drosophilia lacking CD246 do not develop normal gut musculature.

BIOCHEMICAL ACTIVITY

CD246 is a receptor of tyrosine kinase.  Chromosomal translocations affecting CD246 results in production of a variety of fusion proteins by autophosphorylation and the phosphorylation of its substrates in the cytoplasma.  Most fusion proteins have an oligomerization domain resulting in oligomerization of the proteins and constitutive activation.  There is evidence that MAP kinase pathway is involved in a role in neural development.

DISEASE RELEVANCE AND FUNCTION OF CD246 IN INTACT ANIMAL

The wide distribution of CD246 mRNA in fetal murine brains, the absence of large amounts of protein in the adult human brain and recent in vitro evidence suggests a role for this protein in neural distributions in the nervous system.  The expression of 200 kDa CD246 protein has been found in a subtype of B cell lymphoma and in neuroblastoma and rhabdomyosarcoma.  Expression of CD246 fusion proteins is most commonly associated with ALCL.  The most common fusion protein is NPM-ALK and the less common ALK proteins are TPM3-ALK, TFG-ALK, ATIC-ALK, CLTCL-ALK and MSN-ALK.   The chimeric NPM1-ALK protein homodimerizes and the kinase becomes activated and is found to be oncogenic both in vitro and in vivo.  These aberrant CD246 proteins are constitutively phosphorylated probably as a result of dimerisation motifs present within the partner protein which mimics ligand binding to CD246.  The CD246 positve lymphomas appear to have a better prognosis than the CD246 negative ALCL.  Chromosomal abnormalities affecting the CD246 gene and expression of TPM3- and TPM4-ALK, CLTC-ALK and RanBP2-ALK fusion proteins have been detected in inflammatory myofibroblastic tumors.  CD246 plays an important role in brain development and is responsible for 5-10% of non-Hodgkin lymphomas and Hodgkin disease.  A chromosomal aberration involving CD246 is also associated with anaplastic large-cell lymphoma (ALCL) and inflammatory myofibroblastic tumors (IMTs).  CD246 is a marker in the diagnosis of ALCL.


    
  


Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD246: No information.

SUBSTRATES

The substrates for CD246 are SHC, IRS-1, GRB2, phospholipase C, P13 kinase, PKB/AKT and MAP kinases.

ENZYMES WHICH MODIFY CD246: No information.

ADDITIONAL INSIGHTS

CD246, in common with other receptor tyrosine kinases, is involved in chromosomal abnormalities resulting in the formation of oncogenic fusion proteins.  CD246 fusion proteins consist of the N-terminal regions of the various partner proteins and the intracytoplasmic region of CD246.




Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 238Q9UM73
MouseD83002
Antibodies

Revised June 25, 2008


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