AXL receptor tyrosine kinase

AXL
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2C5D, 4RA0
Identifiers
Aliases	AXL, AZF, AZFA, SP3, AZF1, ARK, JTK11, Tyro7, UFO, AXL receptor tyrosine kinase
External IDs	OMIM: 109135 MGI: 1347244 HomoloGene: 7583 GeneCards: AXL
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.2 Start 41,219,223 bp[1] End 41,261,766 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7 A3|7 14.02 cM Start 25,456,698 bp[2] End 25,488,130 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in synovial joint saphenous vein stromal cell of endometrium synovial membrane urethra pericardium popliteal artery right coronary artery left coronary artery vena cava Top expressed in ascending aorta aortic valve belly cord ankle joint lip ankle uterus esophagus dermis endocardial cushion More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding protein kinase activity transferase activity virus receptor activity kinase activity protein heterodimerization activity ATP binding phosphatidylserine binding protein binding transmembrane receptor protein tyrosine kinase activity phosphatidylinositol 3-kinase binding myosin heavy chain binding protein tyrosine kinase activity Wnt-protein binding Cellular component extracellular exosome integral component of membrane host cell surface integral component of plasma membrane cell surface membrane intracellular anatomical structure plasma membrane extracellular space receptor complex Biological process protein kinase B signaling positive regulation of natural killer cell differentiation apoptotic cell clearance negative regulation of lymphocyte activation spermatogenesis negative regulation of apoptotic process signal transduction natural killer cell differentiation negative regulation of interferon-gamma production cellular response to lipopolysaccharide secretion by cell vascular endothelial growth factor receptor signaling pathway substrate adhesion-dependent cell spreading erythrocyte homeostasis negative regulation of tumor necrosis factor production positive regulation of protein kinase B signaling viral process positive regulation of cytokine-mediated signaling pathway cellular response to interferon-alpha forebrain cell migration viral entry into host cell negative regulation of dendritic cell apoptotic process protein phosphorylation cellular response to extracellular stimulus enzyme linked receptor protein signaling pathway positive regulation of pinocytosis negative regulation of neuron apoptotic process vagina development ovulation cycle innate immune response blood vessel remodeling cell maturation dendritic cell differentiation platelet activation cell differentiation immune system process inflammatory response neuron migration phosphorylation cellular response to hydrogen peroxide animal organ regeneration phagocytosis peptidyl-tyrosine phosphorylation negative regulation of cytokine production neutrophil clearance transmembrane receptor protein tyrosine kinase signaling pathway nervous system development Wnt signaling pathway cell migration Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 558 26362 Ensembl ENSG00000167601 ENSMUSG00000002602 UniProt P30530 Q00993 RefSeq (mRNA) NM_001278599 NM_001699 NM_021913 NM_001190974 NM_001190975 NM_009465 RefSeq (protein) NP_001265528 NP_001690 NP_068713 NP_001177903 NP_001177904 NP_033491 Location (UCSC) Chr 19: 41.22 – 41.26 Mb Chr 7: 25.46 – 25.49 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Tyrosine-protein kinase receptor UFO is an enzyme that in humans is encoded by the AXL gene.^[5][6] The gene was initially designated as UFO, in allusion to the unidentified function of this protein.^[7] However, in the years since its discovery, research into AXL's expression profile and mechanism has made it an increasingly attractive target, especially for cancer therapeutics. In recent years, AXL has emerged as a key facilitator of immune escape and drug-resistance by cancer cells, leading to aggressive and metastatic cancers.^[8]

AXL is a cell surface receptor tyrosine kinase, part of the TAM family of kinases including TYRO3 and MERTK.^{[citation needed]}

Gene and protein structure

The Axl gene is evolutionarily conserved between vertebrate species. This gene has two different alternatively spliced transcript variants.^[6]

The protein encoded by this gene is a member of the receptor tyrosine kinase subfamily. Although it is similar to other receptor tyrosine kinases, the Axl protein represents a unique structure of the extracellular region that juxtaposes IgL and FNIII repeats.^[6]

The AXL protein is characterized by an extracellular structure consisting of two fibronectin type 3-like repeats and two immunoglobulin-like repeats along with its intracellular tyrosine kinase domain.

AXL is in close vicinity to the BCL3 oncogene, which is at 19q13.1-q13.2.^[6]

Function

The AXL receptor transduces signals from the extracellular matrix into the cytoplasm by binding growth factors like vitamin K-dependent protein growth-arrest-specific gene 6 (GAS6). It is involved in the stimulation of cell proliferation and survival. Proteolytic cleavage of the AXL extracellular domain by the metalloproteinases ADAM10 and ADAM17 can downregulate this signalling activity.^[9]

Signalling pathways activated downstream of AXL include PI3K-AKT-mTOR, MEKERK, NF-κB, and JAK/STAT.^[10]

This receptor can also mediate cell aggregation by homophilic binding.^[6]

AXL protein is expressed in normal tissues, particularly in bone marrow stroma and myeloid cells, and in tumour cells and tumour vasculature.^[11][12] In cancer, AXL is expressed on the tumor cells as well as adjacent immune cells including dendritic cells, macrophages, and NK cells.

Axl is an inhibitor of the innate immune response. The function of activated AXL in normal tissues includes the efficient clearance of apoptotic material and the dampening of TLR-dependent inflammatory responses and natural killer cell activity.^[13]

AXL is a putative driver of diverse cellular processes that are critical for the development, growth, and spread of tumours, including proliferation, invasiveness and migration, epithelial-to-mesenchymal transition, stemness, angiogenesis, and immune modulation.^[10] AXL has been implicated as a cancer driver and correlated with poor survival in numerous aggressive tumors including triple-negative breast cancer (TNBC), acute myeloid leukemia (AML), non-small-cell lung cancer (NSCLC), pancreatic cancer and ovarian cancer, among others.^[14]

Clinical significance

Axl was first isolated in 1988 and identified as an oncogene in a screen for transforming genes in patients with a chronic myelogenous leukemia- that progressed to 'blast crisis'.^[15] Since then, increased AXL expression has been associated with numerous cancers including lung cancer, breast cancer, pancreatic cancer, ovarian cancer, colon cancer and melanoma among others, and shown to have a strong correlation with poor survival outcomes.^[12]

AXL has been shown to be a key driver of drug-resistance to targeted therapies, immuno therapies and chemotherapy in various animal models. Based on current knowledge of AXL's role in therapy resistance, future studies will help to determine whether AXL has a translational application as a biomarker for predicting therapeutic response to established drugs.

Recently, AXL has been implicated in chronic fibrotic diseases in several organs, including the liver.^[16]

AXL also play an important role in Zika virus and SARS-CoV-2 infection, allowing for entry of the virus into host cells.^{[17] [18]} This phenomenon is known to rely on phosphatidylserine incorporated in the viral envelope during egress, which then binds to AXL via the adapter GAS6. AXL mediates internalization into the endosome from which these viruses escape and initiate replication.

As a drug target

Studies have shown that AXL knockdown leads to downregulation of transcription factors required for EMT, including Slug, Twist, and Zeb1, and to increased expression of E-cadherin.^[19]

Clinical studies

Cancer

Several drugs classified as "AXL inhibitors" have entered clinical trials; however, many target multiple kinase receptors in addition to AXL. The most advanced AXL selective inhibitor is bemcentinib (BGB324 or R428), an oral small molecule currently in multiple Phase II clinical trials for NSCLC, TNBC, AML and melanoma. Bemcentinib is being pursued as monotherapy and as combination therapy with existing and emerging targeted therapies, immunotherapies and chemotherapy.

A monoclonal antibody targeting AXL (YW327.6S2) and an AXL decoy receptor (GL2I.T) are currently in preclinical development. Additionally, an oral AXL inhibitor (TP-0903) is expected to enter Phase 1 clinical trial in November 2016 (in advanced solid tumours: NCT02729298).

Astellas Pharma is currently testing gilteritinib (ASP2215), a dual FLT3-AXL tyrosine kinase inhibitor in acute myeloid leukemia (AML). In 2017, gilteritinib gained FDA orphan drug status for AML.^[20]

These approved drugs and ongoing and pending clinical trials highlight the potentially wide-ranging safety and efficacy of AXL inhibition.^[10]

Interactions

AXL receptor tyrosine kinase has been shown to interact with TENC1.^[21]

References

Further reading

External links

• Human AXL genome location and AXL gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P30530 (Tyrosine-protein kinase receptor UFO) at the PDBe-KB.