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AXL (AXL receptor tyrosine kinase)

Identity

Other namesJTK11
UFO
HGNC (Hugo) AXL
LocusID (NCBI) 558
Location 19q13.2
Location_base_pair Starts at 41732660 and ends at 41767672 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  The diagram depicts the structure of the AXL gene (bottom) roughly aligned with its corresponding functional protein domains (top). Boxes represent individual exons with widths roughly relative to the base-pair length; connecting lines between exon boxes represent introns, which are drawn approximately 10-fold smaller to better align with the protein domains. The open-ended boxes of exons 1 and 20 indicate untranslated regions (not shown). Exon 10, which can be removed via alternative splicing, encodes an extracellular region at the C-terminal end of the second FNIII domain.
Description The human AXL gene is located on chromosome 19q13.2 and encodes 20 exons. Exons 1-10 encode the extracellular domain, which includes a signal peptide (exon 1), two immunoglobulin (Ig) domains (exons 2-3 and 4-5), and two fibronectin type III (FNIII) domains (exons 6-7 and 8-9). Exon 11 encodes a short extracellular region subject to proteolytic cleavage (see protein description), as well as the entire transmembrane domain. Exons 12-20 encode the intracellular domain, which includes the tyrosine kinase domain (exons 13-20) (O'Bryan et al., 1991; Hubbard et al., 2009).
Transcription There are two 4.7 kb mRNA variants of AXL distinguished by the presence or absence of exon 10, a 27 bp region in the C-terminal end of the extracellular domain, via alternative splicing. Both variants exist ubiquitously and at much higher levels in many cancers. Although the longer transcript is more highly expressed in tumor tissue relative to its shorter counterpart, both forms of the protein have the same transforming potential (O'Bryan et al., 1991).

Protein

 
  The diagram on the top depicts the domain organization of the AXL receptor tyrosine kinase. The intracellular kinase domain includes the seven-residue sequence conserved among TAM family receptor tyrosine kinases: at positions 3 and 5 within this conserved sequence, AXL and MERTK contain isoleucine (I) residues, while TYRO3 contains leucine (L) residues. Proteolytic cleavage of residues between the transmembrane and closest FNIII domains renders a soluble isoform of AXL, which contains its fully functioning extracellular domains. The diagram on the bottom depicts the domain structure of GAS6, the AXL ligand. GAS6 is activated by vitamin K-dependent carboxylation of the gamma-carboxyglutamic acid (Gla) domain.
Description The full-length AXL protein contains 894 amino acids and has a molecular weight of 104 kDa. As the extracellular domain contains six N-linked glycosylation sites, two other post-translationally modified forms weighing 120 and 140 kDa -representing partial and complete glycosylation, respectively- have been identified. The extracellular component of the AXL receptor contains two Ig-like domains (aa 37-124 for domain 1, 141-212 for domain 2) followed by two FNIII domains (aa 224-322 for domain 1, 325-428 for domain 2) (O'Bryan et al., 1991). This particular tandem arrangement defines AXL as part of the TAM family of receptor tyrosine kinases (RTKs), which also includes TYRO3 and MERTK (Graham et al., 1994). All three TAM family proteins bind the ligand GAS6, a vitamin K-dependent protein structurally similar to Protein S (PROS1), which activates MERTK and TYRO3 but not AXL (Prasad et al., 2006). Like all TAM family members, each immunoglobulin domain of the AXL receptor provides a binding site for each of the two laminin G-like (LG) domains of GAS6, the only identified ligand for AXL as of yet (Sasaki et al., 2006).
Carboxy-terminal to the second FNIII domain, fourteen amino acids (aa 438-451 in the longer variant) serve as a proteolytic cleavage site, yielding an 80 kD soluble form of AXL with only the extracellular domains of the full-length protein. As this cleavage site translates from exon 11, proteins from both transcript variants are subject to proteolysis. The intact ligand-binding domains in this soluble form highlight its potential role in signal transduction as an inhibitor of the membrane-bound receptor (O'Bryan et al., 1995).
The intracellular tyrosine kinase domain of AXL contains the sequence KW(I/L)A(I/L)ES (aa 714-720), which is conserved among all TAM family RTKs. Within this signature motif, the third and fifth amino acids are isoleucine (I) in both AXL and MERTK, while leucine (L) occupies these positions in TYRO3 (Graham et al., 1994). Activation of the AXL receptor occurs within its intracellular domain and is characterized by the phosphorylation of tyrosine residues at sites that have yet to be defined. MERTK is the only TAM family member with validated tyrosine autophosphorylation sites; AXL also has three tyrosine residues -Y697, Y702, and Y703- conserved in sequence context within its kinase domain, but no evidence exists implicating their role in autophosphorylation (Ling et al., 1996). Numerous mass spectrometry analyses confirm that these and several other tyrosine residues are, in fact, phosphorylated (Hornbeck et al., 2004), and a recent study demonstrated that phosphorylation occurs at Y702 and Y703 upon GAS6 stimulation (Pao-Chun et al., 2009). However, neither of these sites has been shown to directly regulate or interact with the downstream effectors of AXL activation.
Three other tyrosine residues within the AXL intracellular domain -Y779, Y821, and Y866- mediate binding of various substrates, suggesting that they may be more likely candidates for autophosphorylation sites. Y779 partially contributes to binding PI3K, while Y866 plays an integral role in binding PLC. Y821 has been shown to be a critical docking site for multiple substrates, including PI3K, PLC, GRB2, c-SRC, and LCK (Braunger et al., 1997). Despite this evidence, an in vivo study refuted the significance of Y821 in AXL autophosphorylation and activation, as mutants without Y821 display normal GAS6-stimulated tyrosine phosphorylation (Fridell et al., 1996).
Along with conventional ligand-induced dimerization and autophosphorylation, AXL activation can also occur through ligand-independent pathways. AXL overexpression causes homophilic binding between its extracellular domains on neighboring cells and leads to increased phosphorylation of its intracellular domain (Bellosta et al., 1995). AXL also engages in cross-talk with the IL-15 receptor, which transactivates AXL and requires it for survival from TNF-alpha-mediated apoptosis (Budagian et al., 2005).
Expression AXL is expressed throughout all tissue and cell types (O'Bryan et al., 1991). Higher expression is observed in endothelial cells, heart and skeletal muscle, liver, kidney, testis, platelets, myelomonocytic cells, hippocampus, and cerebellum (Neubauer et al., 1994; Bellosta et al., 1995; Graham et al., 1995; Angelillo-Scherrer et al., 2001). Relative to normal expression levels, AXL is increased in a number of disease states as reviewed by Linger et al (2008).
Localisation AXL is a transmembrane receptor tyrosine kinase.
Function Activation of the AXL receptor initiates various signaling pathways involved in cell survival, proliferation, apoptosis inhibition, migration, cell adhesion, and cytokine production. This is mediated via interactions with a spectrum of signaling molecules, including PI3K/Akt, ERK1/ERK2, GRB2, RAS, RAF1, MEK-1, and SOCS-1. Beyond its overexpression and oncogenic potential in numerous cancers, AXL has also been implicated in angiogenesis and metastasis (Linger et al., 2008).
Homology AXL and the two other TAM family members, MERTK and TYRO3, share 31-36% and 54-59% sequence identities in the extracellular and intracellular regions, respectively (Graham et al., 1995).

Mutations

Note Although AXL overexpression is implicated in oncogenesis, no mutations in the gene have been identified as the underlying cause.

Implicated in

Entity Malignancy
Disease The transforming properties of AXL were first identified in patients with chronic myelogenous leukemia (O'Bryan et al., 1991). AXL overexpression has also been reported in glioblastoma, melanoma, osteosarcoma, erythroid and megakaryocytic leukemias, and uterine, colon, prostate, thyroid, ovarian, and liver cancers (Linger et al., 2008).
AXL overexpression positively correlates with tumor metastasis and invasiveness in a number of tumor types, including renal cell carcinoma (Chung et al., 2003), glioblastoma (Hutterer et al., 2008), and breast (Meric et al., 2002), gastric (Wu et al., 2002), lung (Shieh et al., 2005), and prostate cancers (Sainaghi et al., 2005). AXL expression increases in response to both targeted therapeutics and traditional chemotherapy, conferring drug resistance in gastrointestinal stromal tumors (Mahadevan et al., 2007) and acute myeloid leukemia (Hong et al., 2008). Along with other signaling molecules -including some that function with AXL to mediate drug resistance- AXL plays an important role in breast cancer epithelial-to-mesenchymal transition (EMT), a key program in metastasis induction (Gjerdrum et al., 2009).
The effects of AXL inhibition on cancer cells make AXL an attractive target for cancer treatment. In mouse xenografts of human breast cancer, RNAi-mediated AXL inhibition decreases angiogenesis by impairing endothelial cell migration, proliferation, and tube formation (Holland et al., 2005). Antibodies against the extracellular AXL domain decrease tumor growth and invasion in in vitro models of breast and lung cancer (Zhang et al., 2008; Li et al., 2009). More recently, several small molecules have been identified as promising AXL inhibitors: MP470 has cytotoxic effects on gastrointestinal stromal tumors and synergizes with other standard treatments (Mahadevan et al., 2007). In breast cancer, 3-quinolinecarbonitrile compounds decrease motility and invasion (Zhang et al., 2008), and R428 selectively blocks AXL and its ability to promote angiogenesis and metastasis (Holland et al., 2010).
  
Entity Autoimmune disease
Disease Mice devoid of TYRO3, AXL, and MERTK develop autoimmune diseases, including rheumatoid arthritis and lupus, with more pronounced susceptibility to autoimmunity in triple-knockout (relative to single- or double-knockout) TAM mutants (Cohen et al., 2002; Lemke and Lu, 2003). Transgenic mice with ectopic AXL expression develop noninsulin-dependent diabetes mellitus and have increased levels of TNF-alpha (Augustine et al., 1999). In humans, AXL promotes survival of endothelial cells in the synovial joints of patients with rheumatoid arthritis (O'Donnell et al., 1999) and mediates injury-induced chemotaxis and vascular remodeling (Fridell et al., 1998).
  

External links

Nomenclature
HGNC (Hugo)AXL   905
Cards
AtlasAXLID733ch19q13
Entrez_Gene (NCBI)AXL  558  AXL receptor tyrosine kinase
GeneCards (Weizmann)AXL
Ensembl (Hinxton)ENSG00000167601 [Gene_View]  chr19:41732660-41767672 [Contig_View]  AXL [Vega]
ICGC DataPortalENSG00000167601
cBioPortalAXL
AceView (NCBI)AXL
Genatlas (Paris)AXL
WikiGenes558
SOURCE (Princeton)NM_001278599 NM_001699 NM_021913
Genomic and cartography
GoldenPath (UCSC)AXL  -  19q13.2   chr19:41732660-41767672 +  19q13.1   [Description]    (hg19-Feb_2009)
EnsemblAXL - 19q13.1 [CytoView]
Mapping of homologs : NCBIAXL [Mapview]
OMIM109135   
Gene and transcription
Genbank (Entrez)AA021223 AI300772 AI309979 AK309139 AK310881
RefSeq transcript (Entrez)NM_001278599 NM_001699 NM_021913
RefSeq genomic (Entrez)AC_000151 NC_000019 NC_018930 NT_011109 NW_001838496 NW_004929415
Consensus coding sequences : CCDS (NCBI)AXL
Cluster EST : UnigeneHs.590970 [ NCBI ]
CGAP (NCI)Hs.590970
Alternative Splicing : Fast-db (Paris)GSHG0014943
Alternative Splicing GalleryENSG00000167601
Gene ExpressionAXL [ NCBI-GEO ]     AXL [ SEEK ]   AXL [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP30530 (Uniprot)
NextProtP30530  [Medical]
With graphics : InterProP30530
Splice isoforms : SwissVarP30530 (Swissvar)
Catalytic activity : Enzyme2.7.10.1 [ Enzyme-Expasy ]   2.7.10.12.7.10.1 [ IntEnz-EBI ]   2.7.10.1 [ BRENDA ]   2.7.10.1 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)FN3 (PS50853)    IG_LIKE (PS50835)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)   
Domains : Interpro (EBI)Fibronectin_type3 [organisation]   Ig-like_dom [organisation]   Ig-like_fold [organisation]   Ig_sub [organisation]   Ig_V-set [organisation]   Kinase-like_dom [organisation]   Prot_kinase_dom [organisation]   Protein_kinase_ATP_BS [organisation]   Ser-Thr/Tyr_kinase_cat_dom [organisation]   Tyr_kinase_AS [organisation]   Tyr_kinase_cat_dom [organisation]  
Related proteins : CluSTrP30530
Domain families : Pfam (Sanger)fn3 (PF00041)    Pkinase_Tyr (PF07714)    V-set (PF07686)   
Domain families : Pfam (NCBI)pfam00041    pfam07714    pfam07686   
Domain families : Smart (EMBL)FN3 (SM00060)  IG (SM00409)  TyrKc (SM00219)  
DMDM Disease mutations558
Blocks (Seattle)P30530
PDB (SRS)2C5D   
PDB (PDBSum)2C5D   
PDB (IMB)2C5D   
PDB (RSDB)2C5D   
Human Protein AtlasENSG00000167601 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP30530
HPRD00171
IPIIPI00296992   IPI00397361   
Protein Interaction databases
DIP (DOE-UCLA)P30530
IntAct (EBI)P30530
FunCoupENSG00000167601
BioGRIDAXL
InParanoidP30530
Interologous Interaction database P30530
IntegromeDBAXL
STRING (EMBL)AXL
Ontologies - Pathways
Ontology : AmiGOneuron migration  natural killer cell differentiation  phosphatidylserine binding  positive regulation of cytokine-mediated signaling pathway  blood vessel remodeling  transmembrane receptor protein tyrosine kinase activity  protein binding  ATP binding  extracellular space  integral to plasma membrane  phagocytosis  inflammatory response  signal transduction  enzyme linked receptor protein signaling pathway  spermatogenesis  cell surface  forebrain cell migration  platelet activation  cellular response to extracellular stimulus  negative regulation of interferon-gamma production  negative regulation of tumor necrosis factor production  positive regulation of natural killer cell differentiation  secretion by cell  erythrocyte homeostasis  substrate adhesion-dependent cell spreading  cellular response to interferon-alpha  ovulation cycle  apoptotic cell clearance  protein kinase B signaling cascade  negative regulation of neuron apoptotic process  innate immune response  protein heterodimerization activity  cell maturation  negative regulation of lymphocyte activation  positive regulation of protein kinase B signaling cascade  vagina development  cellular response to lipopolysaccharide  dendritic cell differentiation  negative regulation of dendritic cell apoptotic process  
Ontology : EGO-EBIneuron migration  natural killer cell differentiation  phosphatidylserine binding  positive regulation of cytokine-mediated signaling pathway  blood vessel remodeling  transmembrane receptor protein tyrosine kinase activity  protein binding  ATP binding  extracellular space  integral to plasma membrane  phagocytosis  inflammatory response  signal transduction  enzyme linked receptor protein signaling pathway  spermatogenesis  cell surface  forebrain cell migration  platelet activation  cellular response to extracellular stimulus  negative regulation of interferon-gamma production  negative regulation of tumor necrosis factor production  positive regulation of natural killer cell differentiation  secretion by cell  erythrocyte homeostasis  substrate adhesion-dependent cell spreading  cellular response to interferon-alpha  ovulation cycle  apoptotic cell clearance  protein kinase B signaling cascade  negative regulation of neuron apoptotic process  innate immune response  protein heterodimerization activity  cell maturation  negative regulation of lymphocyte activation  positive regulation of protein kinase B signaling cascade  vagina development  cellular response to lipopolysaccharide  dendritic cell differentiation  negative regulation of dendritic cell apoptotic process  
Protein Interaction DatabaseAXL
Wikipedia pathwaysAXL
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)AXL
snp3D : Map Gene to Disease558
SNP (GeneSNP Utah)AXL
SNP : HGBaseAXL
Genetic variants : HAPMAPAXL
Exome VariantAXL
1000_GenomesAXL 
ICGC programENSG00000167601 
Somatic Mutations in Cancer : COSMICAXL 
CONAN: Copy Number AnalysisAXL 
Mutations and Diseases : HGMDAXL
Genomic VariantsAXL  AXL [DGVbeta]
dbVarAXL
ClinVarAXL
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM109135   
MedgenAXL
GENETestsAXL
Disease Genetic AssociationAXL
Huge Navigator AXL [HugePedia]  AXL [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneAXL
Homology/Alignments : Family Browser (UCSC)AXL
Phylogenetic Trees/Animal Genes : TreeFamAXL
Chemical/Protein Interactions : CTD558
Chemical/Pharm GKB GenePA25197
Clinical trialAXL
Cancer Resource (Charite)ENSG00000167601
Other databases
Probes
Litterature
PubMed116 Pubmed reference(s) in Entrez
CoreMineAXL
iHOPAXL

Bibliography

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Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis.
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Expression profile of tyrosine kinases in breast cancer.
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Clinical significance of AXL kinase family in gastric cancer.
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A promiscuous liaison between IL-15 receptor and Axl receptor tyrosine kinase in cell death control.
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PMID 16308569
 
Multiple roles for the receptor tyrosine kinase axl in tumor formation.
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PMID 16230391
 
Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor.
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TAM receptor function in the retinal pigment epithelium.
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A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors.
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Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia.
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Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme.
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AXL is a potential target for therapeutic intervention in breast cancer progression.
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Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling.
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PMID 19815557
 
Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival.
Gjerdrum C, Tiron C, Hoiby T, Stefansson I, Haugen H, Sandal T, Collett K, Li S, McCormack E, Gjertsen BT, Micklem DR, Akslen LA, Glackin C, Lorens JB.
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PMID 20080645
 
R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer.
Holland SJ, Pan A, Franci C, Hu Y, Chang B, Li W, Duan M, Torneros A, Yu J, Heckrodt TJ, Zhang J, Ding P, Apatira A, Chua J, Brandt R, Pine P, Goff D, Singh R, Payan DG, Hitoshi Y.
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PMID 20145120
 
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Contributor(s)

Written02-2010Justine Migdall, Douglas K Graham
Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA

Citation

This paper should be referenced as such :
Migdall, J ; Graham, DK
AXL (AXL receptor tyrosine kinase)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(11):-.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/AXLID733ch19q13.html

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indexed on : Fri Jul 11 17:06:00 CEST 2014

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