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Gene Section
Review
AXL (AXL receptor tyrosine kinase)
Justine Migdall, Douglas K Graham
Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA (JM,
DKG)
Published in Atlas Database: February 2010
Online updated version: http://AtlasGeneticsOncology.org/Genes/AXLID733ch19q13.html
DOI: 10.4267/2042/44895
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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).
Identity
Other names: JTK11; UFO
HGNC (Hugo): AXL
Location: 19q13.2
Transcription
DNA/RNA
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).
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
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.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)
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AXL (AXL receptor tyrosine kinase)
Migdall J, Graham DK
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.
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 membranebound 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
Protein
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 Glike (LG) domains of GAS6, the only identified ligand
for AXL as of yet (Sasaki et al., 2006).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)
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AXL (AXL receptor tyrosine kinase)
Migdall J, Graham DK
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).
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
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 resistanceAXL plays an important role in breast cancer epithelialto-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).
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; AngelilloScherrer 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).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)
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Migdall J, Graham DK
receptor tyrosine kinase Axl and its ligand Gas6 in rheumatoid
arthritis: evidence for a novel endothelial cell survival pathway.
Am J Pathol. 1999 Apr;154(4):1171-80
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 TNFalpha (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).
Angelillo-Scherrer A, de Frutos P, Aparicio C, Melis E, Savi P,
Lupu F, Arnout J, Dewerchin M, Hoylaerts M, Herbert J, Collen
D, Dahlbäck B, Carmeliet P. Deficiency or inhibition of Gas6
causes platelet dysfunction and protects mice against
thrombosis. Nat Med. 2001 Feb;7(2):215-21
Cohen PL, Caricchio R, Abraham V, Camenisch TD, Jennette
JC, Roubey RA, Earp HS, Matsushima G, Reap EA. Delayed
apoptotic cell clearance and lupus-like autoimmunity in mice
lacking the c-mer membrane tyrosine kinase. J Exp Med. 2002
Jul 1;196(1):135-40
Meric F, Lee WP, Sahin A, Zhang H, Kung HJ, Hung MC.
Expression profile of tyrosine kinases in breast cancer. Clin
Cancer Res. 2002 Feb;8(2):361-7
Wu CW, Li AF, Chi CW, Lai CH, Huang CL, Lo SS, Lui WY, Lin
WC. Clinical significance of AXL kinase family in gastric
cancer. Anticancer Res. 2002 Mar-Apr;22(2B):1071-8
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Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11)
This article should be referenced as such:
Migdall J, Graham DK. AXL (AXL receptor tyrosine kinase).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):10651069.
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