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(Received for publication, July 11, 1995) From the
Sky (also called Rse, Brt, and Tyro3) is a member of a subfamily
of related receptor tyrosine kinases, including Axl/Ufo/Ark and
c-Eyk/Mer. We obtained evidence that Gas6 (the product of growth
arrest-specific gene 6) is a ligand of the Sky receptor
tyrosine kinase. Gas6, but not protein S (an anticoagulant protein
structurally similar to Gas6), specifically bound to the soluble form
of Sky (Sky-Fc), composed of the extracellular domain of Sky fused to
the Fc domain of human immunoglobulin G1. The native and recombinant
Gas6, but not protein S, stimulated tyrosine phosphorylation of Sky
ectopically expressed in Chinese hamster ovary cells. Stimulation of
Sky in response to Gas6 was inhibited by Sky-Fc. The half-maximal
concentration of Gas6 that stimulated Sky was about 1 nM.
Thus, Gas6 as a ligand for Sky specifically binds to and stimulates Sky
receptor tyrosine kinase.
Receptor tyrosine kinases play a central role in transducing the
external signals across cell membranes into intracellular signaling
systems and these signals lead to cell proliferation, differentiation,
and other responses(1) . Based on similarities of the sequences
of kinase catalytic domains and the structural motifs in the
extracellular domains, these receptors can be classified into
subfamilies(1) . The members of an Axl/Sky receptor subfamily,
which include Axl (also called Ufo and
Ark)(2, 3, 4) , Sky (also called Rse, Brt,
and Tyro3) (5, 6, 7, 8, 9) , and c-Eyk
(also called Mer)(10, 11) , contain the characteristic
extracellular ligand-binding domain composed of two immunoglobulin-like
motifs and two fibronectin type III motifs. Axl was originally
identified as the oncogene for human myelogenic
leukemia(2, 3) , and the gene for c-Eyk was isolated
as a proto-oncogene for the avian viral oncogene
v-eyk(10) . Overexpression of Axl and Sky led to cell
transformation(2, 9, 12) . As the Axl/Sky
family receptors have an oncogenic potential, they may be involved in
tumor progression and in normal cell proliferation. Northern blot
analysis revealed that the Sky transcripts are predominantly expressed
in the
brain(5, 6, 7, 8, 9) ,
while those for Axl and c-Eyk are more widely distributed in various
tissues(2, 3, 4, 10, 11) . The functional roles of the Axl/Sky subfamily of receptor tyrosine
kinases have been given much attention, especially the identification
of ligands. The ligands for Axl and Sky were recently reported to be
the product of growth arrest-specific gene 6 (Gas6) ( Prior to
investigating the physiological functions of Sky and its reported
ligand protein S, we examined the potential of protein S to bind to Sky
and to stimulate tyrosine phosphorylation of Sky. In contrast to an
earlier report(14) , we found no specific binding of protein S
to Sky or stimulation of Sky tyrosine phosphorylation by protein S.
Gas6, not protein S, did show potent activity to bind to Sky and to
induce the phosphorylation of Sky. We describe here our evidence that
Gas6 is the ligand for Sky.
To determine the binding potential of protein S and Gas6 to
Sky, we prepared a chimeric protein (Sky-Fc) that contains the
extracellular ligand-binding domain of Sky fused to the Fc region of
human immunoglobulin IgG1 heavy chain. Affinity adsorption and
precipitation analysis using Fc fusion proteins in the presence of
Protein A-Sepharose showed that Sky-Fc, but not Met-Fc (a control
chimeric protein composed of the extracellular domain of c-Met and the
Fc region of human IgG1), specifically co-precipitated Gas6 protein (Fig. 1A). On the other hand, protein S was not
co-precipitated by either Sky-Fc or Met-Fc (Fig. 1B).
These observations suggest that Gas6 but not protein S can specifically
bind to the extracellular domain of Sky.
Figure 1:
Binding of Gas6 to Sky-Fc fusion
protein. A, rat Gas6 (2 nM) purified from conditioned
media of VSMC was incubated with Protein A-Sepharose in the absence (lane4) or presence of 5 nM Sky-Fc (lane2) or Met-Fc (lane3) fusion
protein. After centrifugation, the precipitates were run on SDS-PAGE
and the bound Gas6 was visualized by immunoblotting with anti-Gas6
antibody (
Ligands for receptor
tyrosine kinases bind to their cognate receptors, then rapidly
stimulate tyrosine phosphorylation of these receptors. To determine if
Gas6 and/or protein S could stimulate tyrosine phosphorylation of Sky,
we constructed CHO cells stably expressing the full-length Sky receptor
tyrosine kinase. Immunoblot analysis using the anti-Sky antibody raised
against the C-terminal peptide of Sky revealed that the Sky protein
with an apparent molecular mass of 140 kDa was detected in
Sky-transfected (B31) cells, while the parental CHO cells showed no
detectable immunoreactive band (Fig. 2A). Cell surface
biotinylation experiments revealed that a 140-kDa protein
immunoprecipitated with anti-Sky antibody was exposed at the cell
surface (data not shown). The tyrosine phosphorylation of Sky expressed
on B31 cells was assessed by immunoblotting with anti-phosphotyrosine
antibody after immunoprecipitation of the cell lysates with anti-Sky
antibody. As shown in Fig. 2B, phosphorylation of Sky
was induced when the B31 cells were treated with Gas6 (compare lanes1 and 2), but not when treated with
protein S (lane4), while the amount of Sky in the
immunoprecipitates remained unchanged. No immunoreactive band with
anti-phosphotyrosine antibody was detected in the anti-Sky
immunoprecipitates of the parental CHO cells treated with Gas6 (Fig. 2B, lane5). These results
clearly show that Gas6 but not protein S can stimulate tyrosine
phosphorylation of the Sky receptor tyrosine kinase expressed in B31
cells. Additionally, phosphorylation of Sky in response to Gas6 was
almost completely blocked in the presence of excess amounts of Sky-Fc (Fig. 2B, lane3). This means that
Sky phosphorylation was induced by direct interaction between
Gas6 and Sky and not by indirect cross-phosphorylation of Sky by other
receptor tyrosine kinases.
Figure 2:
Tyrosine phosphorylation of Sky on B31
cells in response to purified Gas6. A, immunoblot analysis of
Sky expression on CHO cells and B31 cells. Cell lysates of parental CHO
cells (lane1) and sky cDNA-transfected CHO
cells (B31 cells) (lane2) were run on SDS-PAGE and
immunoblotted with anti-Sky antibody (
To exclude the possibility that the Gas6
preparation purified from VSMC used in this study might be contaminated
by the protein activating Sky, recombinant Gas6 was expressed in COS
cells and examined to observe if it would stimulate Sky
phosphorylation. Recombinant protein S was also expressed and examined,
in parallel experiments. Expression of Gas6 and protein S in culture
supernatants of COS cells transfected with each expression plasmid was
confirmed by immunoblot analysis (Fig. 3A). As shown in Fig. 3B, the culture supernatants of COS cells
expressing recombinant Gas6 induced tyrosine phosphorylation of Sky,
whereas the supernatants of mock-transfected COS cells and the
supernatants of COS cells expressing recombinant protein S had no
detectable activity. These observations also show that Gas6 but not
protein S stimulates Sky tyrosine phosphorylation.
Figure 3:
Tyrosine phosphorylation of Sky on B31
cells in response to recombinant Gas6. A, immunoblot analysis
of recombinant rat Gas6 and human protein S transiently expressed in
COS-7 cells. The culture supernatants of COS cells transfected with rat
Gas6 or human protein S cDNA expression plasmid were concentrated, run
on SDS-PAGE, and immunoblotted with anti-Gas6 or anti-protein S
antibody. B, B31 cells were treated for 10 min at 37 °C
with the culture supernatants of mock-transfected COS cells (lane2) or the cells transfected with human protein S (lane3) or rat Gas6 expression plasmid (lane4). C, effects of EGTA on tyrosine
phosphorylation of Sky in response to Gas6. B31 cells were treated for
10 min at 37 °C with 2 nM recombinant rat Gas6 in the
presence or absence of 10 mM EGTA. In B and C, cell lysates were immunoprecipitated with
Protein S
contains 11 Recombinant Gas6 purified to apparent homogeneity
from the culture medium of COS cells transfected with Gas6 expression
plasmid stimulated Sky phosphorylation in a dose-dependent manner (Fig. 4). Tyrosine phosphorylation of Sky was detectable at 0.5
nM of recombinant Gas6 and the half-maximal stimulation was
obtained at approximately 1 nM. The concentration of Gas6
required for stimulation of Sky is comparable to the K
Figure 4:
Dose-dependent tyrosine phosphorylation of
Sky in response to purified recombinant rat Gas6. Recombinant Gas6 was
purified from the culture supernatants of COS-7 cells transfected with
rat Gas6 expression plasmid. Serum-starved B31 cells were treated for
10 min at 37 °C with the indicated concentrations of purified
recombinant Gas6. Cell lysates were immunoprecipitated and
immunoblotted with
In light of all these findings, we propose that Gas6, but not
protein S, is a ligand for Sky, specifically binding to Sky and
stimulating tyrosine phosphorylation. Our observations differ from
those of Stitt et al.(14) . They reported that protein
S but not Gas6 efficiently binds to and stimulates mouse Sky (Tyro3).
Although the Sky receptor they used was of a different species (mouse
Sky used by Stitt et al.(14) versus human
Sky used in our study), the species difference would not likely explain
the different results in ligand specificity, because sequences of human
and mouse Sky are highly homologous (85% identity within their
extracellular domains). If all results are compiled, human protein S
does bind to mouse Sky (as described by Stitt et al.), but
does not bind to human Sky (as described here). As the purified human
protein S used in our study retained both APC cofactor activity and
inhibitory activity of the prothrombinase complex
activity(20) , it is unlikely that the purified protein S we
used was structurally damaged. Thus, at present we have no valid
explanation for the discrepancy between the results obtained in this
study and those by Stitt et al.(14) . Two different
research groups reported that Gas6 is the ligand for Axl, a receptor
closely related to Sky(13, 14) . The effective dose of
Gas6 to Sky shown in this study is comparable to the reported value for
Gas6-Axl interaction(13) . Thus, Gas6 may be a common ligand
for the two related receptors, Sky and Axl. The binding of a ligand to
two distinct members of a receptor subfamily is also seen for
fibroblast growth factor (FGF) family ligands (acidic FGF and basic
FGF), both of which bind to two members of an FGF receptor subfamily,
Flg and Bek, with similar affinity constants(28) , and the
ligands for Eph family receptors (B61 and EHK1-L), which bind to two
members of an Eph receptor subfamily, Eck and EHK-1, with similar
affinity constants (29) . Although neither the functions of
Gas6 nor the physiological significance of receptor redundancy are well
understood, Gas6 may exhibit diverse functions in a cell and
tissue-dependent manner through two distinct receptors, Sky and Axl,
whose expression patterns differ significantly. Identification of
the ligand for Sky should pave the way to initiate research on the
functional roles of Sky and its ligand Gas6. As Sky is expressed
predominantly in neurons in restricted regions of the brain (6) , future study will focus on the biological function of
Gas6 on neurons. As Sky is also expressed in some extents in other
tissues, such as testis, ovary and kidney, and in certain types of
cells(5, 6, 7, 8, 9, 12) ,
the functional roles of Gas6 to these tissues and cells may be
identified. Gas6 potentiates cell proliferation of VSMC stimulated by
Ca
Volume 270,
Number 39,
Issue of September 29, pp. 22681-22684, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
)and protein S, respectively(13, 14) .
Protein S is a vitamin K-dependent plasma glycoprotein that has
anticoagulant activity by acting as a cofactor of activated protein C
(APC)-catalyzed inactivation of coagulation factors Va and
VIIIa(15) . Gas6, originally identified as a gene product
expressed in response to growth arrest, has structural similarity to
protein S with 42-43% identity (16) and was seen to
function as a potentiating factor for thrombin-induced proliferation of
vascular smooth muscle cells (VSMC)(17) .
Purification of Gas6 and Protein S
Gas6 was
purified from the conditioned medium of rat VSMC, according to the
methods described elsewhere(17) . The purity of Gas6 was
confirmed by SDS-polyacrylamide gel electrophoresis (PAGE)
analysis(17) . Protein S was purified from normal human plasma
by the reported procedures(18, 19) . Based on the
SDS-PAGE analysis, under reducing conditions, the preparations of
protein S used in this study contained almost equal amounts of
thrombin-cleaved and uncleaved protein S(18) . The purified
protein S had APC cofactor activity and also inhibited the activity of
the platelet prothrombinase complex(20) .Expression of Recombinant Gas6 and Protein S
The
cDNA encoding rat Gas6 was obtained as previously
reported(17) . The cDNA encoding human protein S was provided
by Dr. B. Dahlbäck (21) . The cDNAs were
subcloned into the PUC-SR
expression plasmid(22) , and the
constructs were transfected into COS-7 cells using liposome
methods(23) . Cells were cultured for 3 days in serum-free
Dulbecco's modified Eagle's medium with 10 µM sodium menadione bisulfite. Levels of proteins expressed in the
conditioned media (100-1000 ng/ml) were determined by
immunoblotting with anti-Gas6 or anti-protein S antibodies.Antibodies
Rabbit anti-Sky polyclonal antibody
(Sky-C) raised against the C-terminal peptide of human Sky was prepared
and purified as described previously(24) . Rabbit anti-protein
S polyclonal antibody was raised against the purified human protein S,
as described elsewhere(25) . Rabbit anti-Gas6 antiserum was
raised against the purified Gas6. Anti-phosphotyrosine monoclonal
antibody (PY20) was purchased from ICN Biomedicals.Construction and Purification of Fc Fusion
Proteins
The cDNA encoding human Sky was isolated, as reported
elsewhere(5) . The cDNA encoding human c-Met (receptor for
hepatocyte growth factor) was obtained from Dr. G. F. Vande
Woude(26) . The cDNA for the Fc region of human IgG1 was
amplified by polymerase chain reaction, using human placenta cDNA as a
template(27) . The KpnI fragment encoding the entire
extracellular domain (amino acid residues 1-430) of the Sky
protein was fused in-frame with the PCR-amplified cDNA fragment of the
Fc region (residues 216-443) of human IgG1, resulting in the
production of the cDNA coding for the Sky-Fc fusion protein with a
Pro-Gly spacer sequence. In a similar manner, the cDNA for the
extracellular domain (residues 1-941) of c-Met was ligated with
the cDNA encoding the Fc region of human IgG1 to construct the cDNA for
Met-Fc fusion protein with a spacer sequence, Pro-Gly-Val-Pro-Gly. The
fused cDNAs were then subcloned into PUC-SR expression vector (22) and transfected into COS-7 cells, using liposome methods.
The serum-free conditioned media of COS cells were collected for three
days. The Fc fusion proteins were purified by Protein A-Sepharose
(Pharmacia Biotech Inc.) chromatography. Levels of the fusion proteins
expressed in the conditioned media were on an average of 100-200
ng/ml.Binding Assay of Gas6 and Protein S to Fc Fusion
Proteins
Purified rat Gas6 or human protein S at a final
concentration of 2 nM was incubated at 4 °C overnight with
5 nM Sky-Fc or Met-Fc fusion protein and Protein A-Sepharose
(30 µl of 50% slurry) in 200 µl of Hanks' balanced salt
solution containing 20 mM Hepes (pH 7.0), 0.02%
NaN
, and 1% bovine serum albumin. After centrifugation, the
precipitates were washed four times with cold phosphate-buffered saline
(PBS), suspended in SDS sampling buffer (25 mM Tris-HCl, pH
6.5, 5% glycerol, 1% SDS, 144 mM 2-mercaptoethanol, 0.05%
bromphenol blue), and subjected to 8% SDS-PAGE. The gels were then
transferred to polyvinylidene difluoride membrane (Bio-Rad) and the
membrane was blocked with 3% nonfat dry milk in PBS containing 0.05%
Tween 20 and incubated for 1 h at room temperature with anti-Gas6 or
anti-protein S antibody diluted in PBS containing 1% nonfat dry milk
and 0.05% Tween 20. After washing the membrane with PBS, it was
incubated with the horseradish peroxidase-conjugated anti-rabbit IgG
(Amersham Corp.) and immunoreactive bands were visualized using ECL
chemiluminescence reagent (Amersham).Construction of CHO Cell Lines Expressing Sky
A
3.8-kb human sky cDNA (5) was subcloned into the NotI site of the expression vector pRc/RSV (Invitrogen)
containing the neomycin-resistant gene. The resulting plasmid was
transfected into CHO cells using liposome methods, and the
G418-resistant colonies were selected. One of the cell lines (B31) with
high Sky expression, as measured by immunoblot analysis, was selected.Tyrosine Phosphorylation Assay
B31 cells were
plated on 60-mm dishes at a density of 2.5 
10
cells/cm
and cultured in Ham's F-12 medium
supplemented with 10% fetal calf serum. After 16 h, cells were
serum-starved for 3 h and treated with Gas6 or protein S for 10 min at
37 °C, as indicated. Cells were rinsed once with cold PBS
containing 1 mM orthovanadate and lysed with cold lysis buffer
(20 mM Hepes, pH 7.2, 1% Nonidet P-40, 10% glycerol, 50 mM NaF, 1 mM phenylmethylsulfonyl fluoride, 1 mM
orthovanadate, and 10 µg/ml leupeptin). The lysates were
immunoprecipitated with anti-Sky antibody, run on SDS-PAGE, and
immunoblotted with anti-Sky antibody or anti-phosphotyrosine monoclonal
antibody, as described previously(24) .
-Gas6). Lane1 shows the
immunoblot of the purified Gas6 used in this assay. B, protein
S (2 nM) purified from human plasma was treated as in A, and the precipitates were immunoblotted with anti-protein S
antibodies (-PS). Elution positions of rat Gas6 (rGas6) and human protein S (hPS) are indicated by arrows. The upper and lower bands of protein S correspond to
the intact and thrombin-cleaved form, respectively. Molecular sizes
(kDa) of marker proteins are indicated on the left.
-Sky). B,
B31 cells (lanes 1-4) and CHO cells (lanes5 and 6) were treated for 10 min at 37 °C
with 2 nM Gas6 purified from conditioned media of VSMC or
protein S (PS) purified from human plasma, as indicated. In lane3, Gas6 (2 nM) was preincubated with
excess amounts of Sky-Fc (20 nM). Cell lysates were
immunoprecipitated with anti-Sky antibody, run on SDS-PAGE, and
immunoblotted with anti-phosphotyrosine antibody (-pY, upperpanel) or anti-Sky antibody (-Sky, lowerpanel). Elution position
of Sky is indicated by an arrow. Molecular sizes (kDa) of
marker proteins are indicated on the left.
-Sky, run on
SDS-PAGE, and immunoblotted with -pY (upperpanel) or -Sky antibody (lowerpanel), as described in Fig. 2. Elution position
of Sky is indicated by an arrow. Molecular sizes (kDa) of
marker proteins are indicated on the left.
-carboxyglutamic acid (Gla) residues in the N-terminal
Gla domain, one
-hydroxyaspartic acid residue in the first
epidermal growth factor (EGF)-like domain, and three
-hydroxyasparagine residues in three other EGF-like
domains(15) . These modified residues appear to be involved in
Ca binding(15) . As these residues are
conserved in the sequence of Gas6, Gas6 may also bind Ca
ions through these residues(16, 17) . To examine
the effects of Ca
ion on Sky-stimulating activity of
Gas6, recombinant Gas6 was treated with EGTA and lost all activity (Fig. 3C). Therefore, Ca
ion binding
is essential for the conformation and activity of Gas6 to bind to and
stimulate Sky.
value (0.3 nM) of the binding of Gas6 to membranes of
VSMC, for which Gas6 has growth potentiating activity(17) .
-pY (upperpanel) or
-Sky antibody (lowerpanel), as described in Fig. 2. Elution position of Sky is indicated by an arrow. Molecular sizes (kDa) of marker proteins are indicated
on the left. B, relative levels of tyrosine
phosphorylation of Sky are plotted as a function of the concentration
of Gas6 added. The levels of tyrosine phosphorylation of Sky were
calculated by dividing the density of anti-phosphotyrosine
immunoreactive band by the density of anti-Sky immunoreactive band. The
density was evaluated from data in A by NIH image software.
The level of tyrosine phosphorylation of Sky when treated with 10
nM recombinant rat Gas6 was taken as
100%.
-mobilizing growth factors, such as thrombin, and
may be involved in intimal thickening of the vascular wall accompanying
atherosclerosis or restenosis(17) . To develop antagonists for
Gas6 that will aid in overcoming these vascular diseases, it is also
important to clearly define which receptor, Sky or Axl, mediates the
action of Gas6 on VSMC. In addition, it will be interesting to search
for other members of the protein S-related protein family, which may
function as ligands for Sky-related receptors such as c-Eyk.
)
We thank Drs. Y. Fujiki, T. Nakamura, S. Iwanaga, and
M. Ohara for advice and helpful comments, Dr. G. F. Vande Woude for the
human c-Met cDNA, and Dr. B. Dahlbäck for the human
protein S cDNA.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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