MERTK is a receptor tyrosine kinase of the TAM (Tyro3, Axl, MERTK) family, with a defined spectrum of normal expression. However, MERTK is overexpressed or ectopically expressed in a wide variety of cancers, including leukemia, non–small cell lung cancer, glioblastoma, melanoma, prostate cancer, breast cancer, colon cancer, gastric cancer, pituitary adenomas, and rhabdomyosarcomas, potentially resulting in the activation of several canonical oncogenic signaling pathways. These include the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, as well as regulation of signal transducer and activator of transcription family members, migration-associated proteins including the focal adhesion kinase and myosin light chain 2, and prosurvival proteins such as survivin and Bcl-2. Each has been implicated in MERTK physiologic and oncogenic functions. In neoplastic cells, these signaling events result in functional phenotypes such as decreased apoptosis, increased migration, chemoresistance, increased colony formation, and increased tumor formation in murine models. Conversely, MERTK inhibition by genetic or pharmacologic means can reverse these pro-oncogenic phenotypes. Multiple therapeutic approaches to MERTK inhibition are currently in development, including ligand “traps”, a monoclonal antibody, and small-molecule tyrosine kinase inhibitors. Clin Cancer Res; 19(19); 5275–80. ©2013 AACR.

In recent years, therapeutic agents targeting specific molecular aberrations in cancer cells have been effective at prolonging survival in multiple cancer types; however, for the majority of patients with cancer, the oncogenic drivers are complex and identification of additional therapeutic targets has become a major research focus. One potential target is MERTK, a member of the TAM-family of receptor tyrosine kinases, which also includes Axl and Tyro3 (reviewed in ref. 1). The physiologic functions of MERTK have only recently been defined in platelets and macrophages, but its overexpression and potential activation in a wide variety of cancers indicate that MERTK signaling confers an advantage on the tumor cell (2–26). Target validation studies, discussed below, suggest that MERTK inhibition is a viable strategy for decreasing tumor burden in preclinical models. Clinically relevant agents are under development in an effort to add MERTK to the list of effectively targeted proteins in patients with cancer.

Discovery of MERTK

MERTK has been implicated in cancer pathogenesis since it was first cloned from a human B-lymphoblastoid expression library and from a human glioblastoma library (7, 15). Although ectopically expressed in multiple lymphoid leukemia cell lines and patient samples, MERTK is absent from normal B and T lymphocytes, suggesting that MERTK may be an attractive target for childhood acute lymphoblastic leukemia (ALL) therapeutic development (7, 9, 27). MERTK sequencing from human and mouse revealed it to be the human ortholog of the chicken c-eyk gene, the cellular proto-oncogene of v-eyk responsible for the oncogenic properties of the RPL30 avian retrovirus, which induces lymphomas, sarcomas, and other tumor types in chickens in vivo (28, 29). Unbiased gain-of-function retroviral insertion screens have also identified the oncogenic role of MERTK (30).

MERTK chimeric receptor signaling

Following cloning of the MERTK cDNA, multiple groups investigated the signaling pathways downstream of MERTK activation (Fig. 1). As a ligand had not yet been identified, early studies used receptor chimeras with the intracellular domain of MERTK fused to the extracellular domain of proteins with a known ligand or dimerization capability. An early strategy combined the transmembrane and cytoplasmic domains of MERTK with the extracellular domain of human colony-stimulating factor 1 (CSF-1) receptor (Fms; ref. 15). In this model, CSF-1 treatment induced MERTK autophosphorylation, transformed NIH 3T3 cells, and activated phospholipase Cγ, phosphatidylinositol 3-kinase (PI3K), and p70 S6 kinase. Recruitment of growth factor receptor binding protein 2 (Grb2) and phosphorylation of Src homology and collagen (Shc) led to Raf-1, mitogen-activated protein/extracellular signal–regulated kinase (MEK), and extracellular signal-regulated kinase (Erk) activation.

Figure 1.

The MERTK Signaling Network. Multiple pro-oncogenic signaling pathways have been implicated downstream of MERTK activation. These include pathways promoting survival, increasing migration, and inhibiting apoptosis. The ligands Gas6, protein S, Tubby, Tulp1, and Galectin-3 all induce MERTK autophosphorylation to initiate the signaling cascades depicted below. More recently, MERTK has been shown to be regulated by two miRNAs, miR126 and miR335, and may also have direct effects on gene transcription. Inhibitors of MERTK, including ligand traps, a monoclonal antibody, and small molecule inhibitors, are currently in preclinical development.

Figure 1.

The MERTK Signaling Network. Multiple pro-oncogenic signaling pathways have been implicated downstream of MERTK activation. These include pathways promoting survival, increasing migration, and inhibiting apoptosis. The ligands Gas6, protein S, Tubby, Tulp1, and Galectin-3 all induce MERTK autophosphorylation to initiate the signaling cascades depicted below. More recently, MERTK has been shown to be regulated by two miRNAs, miR126 and miR335, and may also have direct effects on gene transcription. Inhibitors of MERTK, including ligand traps, a monoclonal antibody, and small molecule inhibitors, are currently in preclinical development.

Close modal

Another MERTK chimeric protein was made by fusing the extracellular domain of CD8 to the intracellular domain of MERTK creating a constitutively active MERTK chimera (31). This MERTK chimera conferred an interleukin 3 (IL-3)–independent phenotype to Ba/F3 pro-B lymphocytes. The Grb2, MEK1, and Erk pathways as well as PI3K were also activated. NF-κB–mediated transcription was increased as assessed by a luciferase-reporter assay with potential activation of antiapoptotic signaling in tumor cells (reviewed in ref. 32). The p38 pathway was also activated and p38 inhibition decreased proliferation in MERTK chimeric Ba/F3 cells. Similar to NF-κB, p38 has complex effects on proliferation, migration, and survival in cancer cells (reviewed in ref. 33).

Finally, our group constructed a chimeric receptor composed of the extracellular and transmembrane domains of the EGF receptor (EGFR) fused to the intracellular domain of MERTK (34). Ligand activation prevented apoptosis in the myeloblast-like 32D cells promoting IL-3-independence and stimulated Erk, Akt, and p38 activity. In this model, MERTK signaling had a primary role in cell survival and cytoskeletal alterations without a substantial effect on proliferation.

MERTK ligands

Although studies using chimeric receptors provided important information on MERTK signaling, identification of authentic MERTK ligands permitted analysis in a more physiologic context. The first ligand described was Gas6, identified by purification of Axl-activating conditioned media. Gas6 binds MERTK, but with 3- to 10-fold lower affinity (35, 36). Subsequently, protein S was identified as a MERTK ligand that did not activate Axl (37, 38). Both ligands are secreted by multiple cell types and are present in human blood, although total protein S levels are 1,000-fold higher; however, modifications of protein S may be necessary for it to activate Mer (39–41). More recently, a novel phagocytosis-based functional cloning screening strategy identified 3 new MERTK ligands: tubby, tubby-like protein 1 (Tulp1), and galectin-3 (42, 43). All known MERTK ligands induce MERTK autophosphorylation, although to date, roles for tubby, Tulp1, and galectin-3 have not been studied in MERTK-driven cancers. However, overexpression of galectin-3 has been shown in many cancers and galectin-3 is known to play roles in a wide variety of oncogenic processes, consistent with the possibility that these phenotypes may be mediated by MERTK signaling (44).

MERTK signaling in leukemia

The ectopic expression of MERTK in pediatric ALL led our group to investigate full-length MERTK receptor oncogenic signaling in lymphocytes (9, 45). A transgenic model was made expressing MERTK from the Vav promoter; lymphocytes at all stages expressed MERTK. Lymphoblastic leukemia and lymphomas resulted from this ectopic MERTK expression and stimulation of these cells with Gas6 induced MERTK autophosphorylation and downstream activation of Erk1/2 and Akt. In human T-cell lymphoblastic leukemia cell lines, Gas6 also activated MERTK, Erk1/2, Akt, STAT5, and STAT6 (10). STAT activation within tumor cells contributes to prosurvival phenotypes (46–48). MERTK knockdown by short hairpin RNA (shRNA) resulted in decreased levels of phospho-STAT5 and phospho-Erk. In addition, in acute myeloid leukemia cells that did not express Axl or Tyro3, Gas6 activated MERTK and resulted in the phosphorylation and activation of Erk1/2, p38, MSK1, cAMP-responsive element binding protein (CREB), activating transcription factor 1 (ATF1), Akt, and STAT6 (49). shRNA knockdown of MERTK reduced the activation of p38, Erk, and CREB, further strengthening these signaling findings. Taken together, these studies broaden and define endogenous MERTK signaling pathways.

MERTK signaling in solid tumors

MERTK signaling observed in leukemia cells is also seen in solid tumor cells; additional novel downstream effectors have also been identified. In non–small cell lung cancer, p38, Erk1/2, GSK3α/β, MEK1/2, Akt, mTOR, CREB, and ATF1 phosphorylation were all induced following Gas6 addition (23). shRNA-mediated MERTK inhibition resulted in decreased levels of CREB, Bcl-xL, survivin, and phospho-Akt, and increased levels of Bcl-2, in response to serum starvation. These results suggest additional mechanisms by which MERTK may impact tumor cell survival. In glioblastoma cells, shRNA mediated reduction of MERTK protein expression and also decreased levels of phosphorylated Erk and Akt (16). In addition, MERTK expression correlated with Nestin and Sox2 expression in a glioblastoma spheroid culture model, indicating possible roles for MERTK maintaining cells in an undifferentiated state (18). In melanoma, Gas6-induced MERTK activation resulted in p38, ERK1/2, GSK3α/β, Akt, AMPK, STAT5, CHK-2, focal adhesion kinase (FAK), and STAT6 phosphorylation, whereas overexpression of MERTK increased the levels of phospho-Akt (21, 22). Inhibition of MERTK by shRNA prevented the Gas6-induced increase of pAkt, pERK1/2, and pSTAT6, decreased basal phosphorylation of Akt, mTOR, and p70S6 kinase, increased PARP cleavage, and decreased CDC42 activity. In prostate cancer cells, MERTK associates with and facilitates the activation of Ack1, a non–receptor tyrosine kinase. This process results in an Ack activity-dependent degradation of the Wwox tumor suppressor, suggesting yet another oncogenic mechanism, that is, control of a tumor suppressor (2). An FMS-MERTK chimera expressed in a prostate cancer cell line induced Raf, MEK1/2, p90RSK, Erk1/2, and Akt phosphorylation and increased c-Fos and c-Jun transcription factor expression (25).

MERTK migration and cellular traffic

MERTK signaling has been implicated in tumor cell migration and invasion. In non–small cell lung cancer cells, FAK is phosphorylated in response to Gas6 (23). Both total and phosphorylated FAK and RhoA increase, whereas total and phosphorylated myosin light chain 2 are decreased in glioblastoma cells in response to shRNA-mediated MERTK inhibition, with impaired migration (17, 18). Melanoma cell migration and invasion are also decreased by shRNA MERTK expression (21, 22). MERTK's physiologic role in ingesting apoptotic material in macrophages is an action that is in part dependent on a MERTK:Vav activation process that stimulates Rac CDC42 and Rho GDP to GTP exchange (50). With respect to cellular trafficking, a recent report links MERTK action to EGFR surface levels (51). In the absence of MERTK, EGF treatment induced a higher rate of EGFR internalization and degradation, resulting in decreased levels of EGFR on the cell surface and reducing downstream signaling. Related to the concept of receptor trafficking, a recent study found MERTK to be located not only at the cell surface, but also in the nucleus. Consensus nuclear localization sequences have also been identified in the MERTK gene (52). This raises the possibility that MERTK may have effects on gene transcription.

Tumor biology and target validation

Many studies have used shRNA to show critical oncogenic roles for MERTK in a variety of tumor types. In T-cell acute lymphoblastic leukemia, shRNA against MERTK resulted in increased apoptosis, decreased methylcellulose colony formation, increased sensitivity to cytotoxic chemotherapies, and delayed disease onset with increased survival in a murine leukemia model (9, 10). Similarly, in acute myeloid leukemia, MERTK inhibition resulted in increased apoptosis, decreased colony formation, and increased survival in a mouse model (49). In glioblastoma, MERTK shRNA increased apoptosis and autophagy, decreased colony formation, increased chemosensitivity, altered morphology, and decreased migration (16–18). In non–small cell lung cancer, MERTK inhibition increased apoptosis, decreased colony formation, increased chemosensitivity, and decreased tumor formation in a mouse model (23). shRNA-mediated inhibition of MERTK in melanoma cell lines resulted in increased cell death, decreased proliferation, decreased colony formation in soft agar, decreased migration, and decreased tumor formation in xenografts (21, 22).

MERTK knockdown in breast cancer cells resulted in decreased formation of metastases and inhibited endothelial cell recruitment in mouse models (12). In breast cancer, miR-126 and miR-335 negatively regulate MERTK expression; loss of these miRNAs contributes to breast cancer progression and metastasis. Mechanistically, miR-126 loss increased MERTK expression. Increased MERTK was followed by extracellular domain cleavage, and soluble MERTK was postulated to act as a ligand sink, sequestering Gas6 and preventing activation of TAM receptors on migrating endothelial cells. Decreased Gas6-induced signaling in endothelial cells increased their migration, resulting in tumor-associated angiogenesis.

Inappropriate or overexpression of MERTK, one of its ligands, or both, has been the most studied mechanism linking MERTK and cancer. However, recent studies in multiple myeloma, melanoma, renal cancer, and head and neck cancer have also identified mutation of MERTK as another possible mechanism (21, 53, 54). Mutation has been recognized as a common method of activating multiple other receptor tyrosine kinases, and it will be interesting to determine the frequency of and functional effects of these recently discovered MERTK mutations.

Therapeutics in development

One strategy to inhibit MERTK is to use a ligand trap, consisting of the extracellular domain of MERTK or an antibody against Gas6, to prevent ligand-dependent MERTK activation (3). A monoclonal antibody against MERTK has been used to decrease the levels of MERTK protein on the surface of glioblastoma cells, resulting in decreased tumor cell migration in vitro (17). In addition, several multikinase small-molecule inhibitors have been shown to have inhibitory effects against MERTK, including sunitinib, BMS-777607, R-428, and Compound-52 (55–58). Recently, several MERTK-selective small-molecule inhibitors have been developed using structure-aided design algorithms. The first of these, UNC569, is a pyrazolopyrimidine derivative that functions as a competitive ATP inhibitor (59). It is highly selective for MERTK, is orally bioavailable, has a favorable pharmacokinetic profile, and has shown promising preclinical activity against leukemia in vitro. A second-generation compound, UNC1062, is a pyrazolopyrimidine sulfonamide derivative of UNC569, which has reduced human ether-a-go-go-related gene potassium channel activity and therefore a more favorable toxicity profile (60). This compound has shown promising preclinical activity in a melanoma model, blocking MERTK activation and downstream signaling via STAT6, Erk, and Akt, increasing apoptosis, decreasing colony formation in soft agar, and decreasing collagen matrix invasion (22).

The MERTK tyrosine kinase has been linked to the pathogenesis of cancer since it was first discovered by expression cloning from a neoplastic cell nearly two decades ago. It has since been shown to activate a wide variety of pro-oncogenic signaling pathways in an ever-expanding list of human cancer types. Signaling pathways, including those involving MAPK and p38, PI3K, Janus-activated kinase (JAK)/STAT, FAK/RhoA/MLC2, and Bcl-2 family members, contribute to increased proliferation and migration, and decreased apoptosis and chemosensitivity. Several types of MERTK inhibitors are currently in development, including ligand traps, a monoclonal antibody, and small-molecule tyrosine kinase inhibitors. Such agents are designed to exploit the selective requirement for MERTK in tumor cells. Although MERTK was infrequently studied in the first decade after its discovery due to a lack of understanding about ligand and cellular biology, this is changing due to recent evidence linking MERTK to oncogenic progression. The hope is that these efforts will result in clinically available MERTK-targeted therapeutics in the near future, as well as a further understanding of how best to deploy them.

D. DeRyckere, H.S. Earp, and D.K. Graham hold equity in Meryx Incorporated. No potential conflicts of interest were disclosed by the other author.

Conception and design: C.T. Cummings, H.S. Earp, D.K. Graham

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): C.T. Cummings

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): C.T. Cummings, D.K. Graham

Writing, review, and/or revision of the manuscript: C.T. Cummings, D. DeRyckere, H.S. Earp, D.K. Graham

Study supervision: D.K. Graham

This work was supported in part by a grant from the NIH (RO1CA137078; to D.K. Graham).

1.
Linger
RM
,
Keating
AK
,
Earp
HS
,
Graham
DK
. 
TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer
.
Adv Cancer Res
2008
;
100
:
35
83
.
2.
Mahajan
NP
,
Whang
YE
,
Mohler
JL
,
Earp
HS
. 
Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox
.
Cancer Res
2005
;
65
:
10514
23
.
3.
Sather
S
,
Kenyon
KD
,
Lefkowitz
JB
,
Liang
X
,
Varnum
BC
,
Henson
PM
, et al
A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation
.
Blood
2007
;
109
:
1026
33
.
4.
Angelillo-Scherrer
A
,
Burnier
L
,
Flores
N
,
Savi
P
,
DeMol
M
,
Schaeffer
P
, et al
Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy
.
J Clin Invest
2005
;
115
:
237
46
.
5.
Scott
RS
,
McMahon
EJ
,
Pop
SM
,
Reap
EA
,
Caricchio
R
,
Cohen
PL
, et al
Phagocytosis and clearance of apoptotic cells is mediated by MER
.
Nature
2001
;
411
:
207
11
.
6.
Camenisch
TD
,
Koller
BH
,
Earp
HS
,
Matsushima
GK
. 
A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock
.
J Immunol
1999
;
162
:
3498
503
.
7.
Graham
DK
,
Dawson
TL
,
Mullaney
DL
,
Snodgrass
HR
,
Earp
HS
. 
Cloning and mRNA expression analysis of a novel human protooncogene, c-mer
.
Cell Growth Differ
1994
;
5
:
647
57
.
8.
Yeoh
EJ
,
Ross
ME
,
Shurtleff
SA
,
Williams
WK
,
Patel
D
,
Mahfouz
R
, et al
Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling
.
Cancer Cell
2002
;
1
:
133
43
.
9.
Graham
DK
,
Salzberg
DB
,
Kurtzberg
J
,
Sather
S
,
Matsushima
GK
,
Keating
AK
, et al
Ectopic expression of the proto-oncogene Mer in pediatric T-cell acute lymphoblastic leukemia
.
Clin Cancer Res
2006
;
12
:
2662
9
.
10.
Brandão
LN
,
Winges
A
,
Christoph
S
,
Sather
S
,
Migdall-Wilson
J
,
Schlegel
J
, et al
Inhibition of MerTK increases chemosensitivity and decreases oncogenic potential in T-cell acute lymphoblastic leukemia
.
Blood Cancer J
2013
;
3
:
e101
.
11.
Tavazoie
SF
,
Alarcon
C
,
Oskarsson
T
,
Padua
D
,
Wang
Q
,
Bos
PD
, et al
Endogenous human microRNAs that suppress breast cancer metastasis
.
Nature
2008
;
451
:
147
52
.
12.
Png
KJ
,
Halberg
N
,
Yoshida
M
,
Tavazoie
SF
., 
A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells
.
Nature
2011
;
481
:
190
4
.
13.
Watanabe
T
,
Kobunai
T
,
Yamamoto
Y
,
Matsuda
K
,
Ishihara
S
,
Nozawa
K
, et al
Differential gene expression signatures between colorectal cancers with and without KRAS mutations: crosstalk between the KRAS pathway and other signalling pathways
.
Eur J Cancer
2011
;
47
:
1946
54
.
14.
Wu
CW
,
Li
AF
,
Chi
CW
,
Lai
CH
,
Huang
CL
,
Lo
SS
, et al
Clinical significance of AXL kinase family in gastric cancer
.
Anticancer Res
2002
;
22
:
1071
8
.
15.
Ling
L
,
Kung
HJ
. 
Mitogenic signals and transforming potential of Nyk, a newly identified neural cell adhesion molecule-related receptor tyrosine kinase
.
Mol Cell Biol
1995
;
15
:
6582
92
.
16.
Keating
AK
,
Kim
GK
,
Jones
AE
,
Donson
AM
,
Ware
K
,
Mulcahy
JM
, et al
Inhibition of Mer and Axl receptor tyrosine kinases in astrocytoma cells leads to increased apoptosis and improved chemosensitivity
.
Mol Cancer Ther
2010
;
9
:
1298
307
.
17.
Rogers
AE
,
Le
JP
,
Sather
S
,
Pernu
BM
,
Graham
DK
,
Pierce
AM
, et al
Mer receptor tyrosine kinase inhibition impedes glioblastoma multiforme migration and alters cellular morphology
.
Oncogene
2012
;
31
:
4171
81
.
18.
Wang
Y
,
Moncayo
G
,
Morin
P
 Jr
,
Xue
G
,
Grzmil
M
,
Lino
MM
, et al
Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme
.
Oncogene
2013
;
32
:
872
82
.
19.
Ek
S
,
Högerkorp
CM
,
Dictor
M
,
Ehinger
M
,
Borrebaeck
CA
. 
Mantle cell lymphomas express a distinct genetic signature affecting lymphocyte trafficking and growth regulation as compared with subpopulations of normal human B cells
.
Cancer Res
2002
;
62
:
4398
405
.
20.
Tworkoski
K
,
Singhal
G
,
Szpakowski
S
,
Zito
CI
,
Bacchiocchi
A
,
Muthusamy
V
, et al
Phosphoproteomic screen identifies potential therapeutic targets in melanoma
.
Mol Cancer Res
2011
;
9
:
801
12
.
21.
Tworkoski
KA
,
Platt
J
,
Bacchiocchi
A
,
Bosenberg
M
,
Boggon
TJ
,
Stern
DF
. 
MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL
.
Pigment Cell Melanoma Res
2013
;
26
:
527
41
.
22.
Schlegel
J
,
Sambade
MJ
,
Sather
S
,
Moschos
SJ
,
Tan
AC
,
Winges
A
, et al
MERTK receptor tyrosine kinase is a therapeutic target in melanoma
.
J Clin Invest
2013
;
123
:
2257
67
23.
Linger
RM
,
Cohen
RA
,
Cummings
CT
,
Sather
S
,
Migdall-Wilson
J
,
Middleton
DH
, et al
Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer
.
Oncogene.
2012 Aug 13
.
[Epub ahead of print]
24.
Evans
CO
,
Young
AN
,
Brown
MR
,
Brat
DJ
,
Parks
JS
,
Neish
AS
, et al
Novel patterns of gene expression in pituitary adenomas identified by complementary deoxyribonucleic acid microarrays and quantitative reverse transcription-polymerase chain reaction
.
J Clin Endocrinol Metab
2001
;
86
:
3097
107
.
25.
Wu
YM
,
Robinson
DR
,
Kung
HJ
. 
Signal pathways in up-regulation of chemokines by tyrosine kinase MER/NYK in prostate cancer cells
.
Cancer Res
2004
;
64
:
7311
20
.
26.
Khan
J
,
Bittner
ML
,
Saal
LH
,
Teichmann
U
,
Azorsa
DO
,
Gooden
GC
, et al
cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene
.
Proc Natl Acad Sci U S A
1999
;
96
:
13264
9
.
27.
Graham
DK
,
Bowman
GW
,
Dawson
TL
,
Stanford
WL
,
Earp
HS
,
Snodgrass
HR
. 
Cloning and developmental expression analysis of the murine c-mer tyrosine kinase
.
Oncogene
1995
;
10
:
2349
59
.
28.
Jia
R
,
Mayer
BJ
,
Hanafusa
T
,
Hanafusa
H
. 
A novel oncogene, v-ryk, encoding a truncated receptor tyrosine kinase is transduced into the RPL30 virus without loss of viral sequences
.
J Virol
1992
;
66
:
5975
87
.
29.
Jia
R
,
Hanafusa
H
. 
The proto-oncogene of v-eyk (v-ryk) is a novel receptor-type protein tyrosine kinase with extracellular Ig/GN-III domains
.
J Biol Chem
1994
;
269
:
1839
44
.
30.
Lierman
E
,
Van Miegroet
H
,
Beullens
E
,
Cools
J
. 
Identification of protein tyrosine kinases with oncogenic potential using a retroviral insertion mutagenesis screen
.
Haematologica
2009
;
94
:
1440
4
.
31.
Georgescu
MM
,
Kirsch
KH
,
Shishido
T
,
Zong
C
,
Hanafusa
H
. 
Biological effects of c-Mer receptor tyrosine kinase in hematopoietic cells depend on the Grb2 binding site in the receptor and activation of NF-kappaB
.
Mol Cell Biol
1999
;
19
:
1171
81
.
32.
Karin
M
. 
Nuclear factor-kappaB in cancer development and progression
.
Nature
2006
;
441
:
431
6
.
33.
Wagner
EF
,
Nebreda
AR
. 
Signal integration by JNK and p38 MAPK pathways in cancer development
.
Nat Rev Cancer
2009
;
9
:
537
49
.
34.
Guttridge
KL
,
Luft
JC
,
Dawson
TL
,
Kozlowska
E
,
Mahajan
NP
,
Varnum
B
, et al
Mer receptor tyrosine kinase signaling: prevention of apoptosis and alteration of cytoskeletal architecture without stimulation or proliferation
.
J Biol Chem
2002
;
277
:
24057
66
.
35.
Chen
J
,
Carey
K
,
Godowski
PJ
. 
Identification of Gas6 as a ligand for Mer, a neural cell adhesion molecule related receptor tyrosine kinase implicated in cellular transformation
.
Oncogene
1997
;
14
:
2033
9
.
36.
Fisher
PW
,
Brigham-Burke
M
,
Wu
SJ
,
Luo
J
,
Carton
J
,
Staquet
K
, et al
A novel site contributing to growth-arrest-specific gene 6 binding to its receptors as revealed by a human monoclonal antibody
.
Biochem J
2005
;
387
:
727
35
.
37.
Nagata
K
,
Ohashi
K
,
Nakano
T
,
Arita
H
,
Zong
C
,
Hanafusa
H
, et al
Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases
.
J Biol Chem
1996
;
271
:
30022
7
.
38.
Prasad
D
,
Rothlin
CV
,
Burrola
P
,
Burstyn-Cohen
T
,
Lu
Q
,
Garcia de Frutos
P
, et al
TAM receptor function in the retinal pigment epithelium
.
Mol Cell Neurosci
2006
;
33
:
96
108
.
39.
Manfioletti
G
,
Brancolini
C
,
Avanzi
G
,
Schneider
C
. 
The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade
.
Mol Cell Biol
1993
;
13
:
4976
85
.
40.
Balogh
I
,
Hafizi
S
,
Stenhoff
J
,
Hansson
K
,
Dahlbäck
B
. 
Analysis of Gas6 in human platelets and plasma
.
Arterioscler Thromb Vasc Biol
2005
;
25
:
1280
6
.
41.
Uehara
H
,
Shacter
E
. 
Auto-oxidation and oligomerization of protein S on the apoptotic cell surface is required for Mer tyrosine kinase-mediated phagocytosis of apoptotic cells
.
J Immunol
2008
;
180
:
2522
30
.
42.
Caberoy
NB
,
Zhou
Y
,
Li
W
. 
Tubby and tubby-like protein 1 are new MerTK ligands for phagocytosis
.
EMBO J
2010
;
29
:
3898
910
.
43.
Caberoy
NB
,
Alvarado
G
,
Bigcas
JL
,
Li
W
. 
Galectin-3 is a new MerTK-specific eat-me signal
.
J Cell Physiol
2012
;
227
:
401
7
.
44.
Newlaczyl
AU
,
Yu
LG
. 
Galectin-3–a jack-of-all-trades in cancer
.
Cancer Lett
2011
;
313
:
123
8
.
45.
Keating
AK
,
Salzberg
DB
,
Sather
S
,
Liang
X
,
Nickoloff
S
,
Anwar
A
, et al
Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase
.
Oncogene
2006
;
25
:
6092
100
.
46.
Bruns
HA
,
Kaplan
MH
. 
The role of constitutively active Stat6 in leukemia and lymphoma
.
Crit Rev Oncol Hematol
2006
;
57
:
245
53
.
47.
Ferbeyre
G
,
Moriggl
R
. 
The role of Stat5 transcription factors as tumor suppressors or oncogenes
.
Biochim Biophys Act
2011
;
1815
:
104
14
.
48.
Yu
H
,
Pardoll
D
,
Jove
R
. 
STATs in cancer inflammation and immunity: a leading role for STAT3
.
Nat Rev Cancer
2009
;
9
:
798
809
.
49.
Lee-Sherick
AB
,
Eisenman
K
,
Sather
S
,
McGranahan
A
,
Armistead
PM
,
McGary
CS
, et al
Aberrant Mer receptor tyrosine kinase expression contributes to leukemogenesis in acute myeloid leukemia
.
Oncogene
. 
2013 Mar 11
.
[Epub ahead of print]
.
50.
Mahajan
NP
,
Earp
HS
. 
An SH2 domain-dependent, phosphotyrosine-independent interaction between Vav1 and the Mer receptor tyrosine kinase: a mechanism for localizing guanine nucleotide-exchange factor action
.
J Biol Chem
2003
;
278
:
42596
603
.
51.
Komurov
K
,
Padron
D
,
Cheng
T
,
Roth
M
,
Rosenblatt
KP
,
White
MA
. 
Comprehensive mapping of the human kinome to epidermal growth factor receptor signaling
.
J Biol Chem
2010
;
285
:
21134
42
.
52.
Migdall-Wilson
J
,
Bates
C
,
Schlegel
J
,
Brandão
L
,
Linger
RM
,
DeRyckere
D
, et al
Prolonged exposure to a Mer ligand in leukemia: Gas6 favors expression of a partial Mer glycoform and reveals a novel role for Mer in the nucleus
.
PLoS ONE
2012
;
7
:
e31635
.
53.
Greenman
C
,
Stephens
P
,
Smith
R
,
Dalgliesh
GL
,
Hunter
C
,
Bignell
G
, et al
Patterns of somatic mutation in human cancer genomes
.
Nature
2007
;
446
:
153
8
.
54.
Hucthagowder
V
,
Meyer
R
,
Mullins
C
,
Nagarajan
R
,
DiPersio
JF
,
Vij
R
, et al
Resequencing analysis of the candidate tyrosine kinase and RAS pathway gene families in multiple myeloma
.
Cancer Genet
2012
;
205
:
474
8
.
55.
Mollard
A
,
Warner
SL
,
Call
LT
,
Wade
ML
,
Bearss
JJ
,
Verma
A
, et al
Design, synthesis and biological evaluation of a series of novel Axl kinase inhibitors
.
ACS Med Chem Lett
2011
;
2
:
907
12
.
56.
Schroeder
GM
,
An
Y
,
Cai
ZW
,
Chen
XT
,
Clark
C
,
Cornelius
LA
, et al
Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily
.
J Med Chem
2009
;
52
:
1251
4
.
57.
Holland
SJ
,
Pan
A
,
Franci
C
,
Hu
Y
,
Chang
B
,
Li
W
, et al
R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer
.
Cancer Res
2010
;
70
:
1544
54
.
58.
Huang
X
,
Finerty
P
 Jr
,
Walker
JR
,
Butler-Cole
C
,
Vedadi
M
,
Schapira
M
, et al
Structural insights into the inhibited states of the Mer receptor tyrosine kinase
.
J Struct Biol
2009
;
165
:
88
96
.
59.
Liu
J
,
Yang
C
,
Simpson
C
,
Deryckere
D
,
Van Deusen
A
,
Miley
MJ
, et al
Discovery of novel small molecule Mer kinase inhibitors for the treatment of pediatric acute lymphoblastic leukemia
.
ACS Med Chem Lett
2012
;
3
:
129
34
.
60.
Liu
J
,
Zhang
W
,
Stashko
M
,
Deryckere
D
,
Cummings
CT
,
Hunter
D
, et al
UNC1062, a new and potent Mer inhibitor
.
Eur J Med Chem.
2013 Apr
.
[Epub ahead of print]
.