OSM Receptor

22 Pages·1.372 MB·English

by  Rose T.M., Bruce A.G.

OSM Receptor
Timothy M. Rose* and A. Gregory Bruce
Department of Pathobiology, School of Public Health and Community Medicine,
University of Washington, Box 357238, Seattle, WA 98195, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.17005.
SUMMARY includes the IL-6(cid:11) receptor (IL-6R(cid:11)) (Bazan, 1990).
Ligand binding to this class of receptors is char-
OncostatinM(OSM),amemberoftheIL-6familyof acterized by low-affinity binding to an (cid:11) receptor
cytokines,interactswithlow-affinityreceptorsubunit subunit which is converted to high affinity by further
monomers and high-affinity heterodimeric receptor association of an additional receptor component or
complexes composed of members of the class I cyto- components involved in signal transduction, usually
kine receptor family. Important species-specific dif- refered to as converting or (cid:12) receptor subunits.
ferencesinreceptorbindinghavebeenidentified.OSM Binding studies demonstrated that gp130 is the low-
binds directly with low-affinity to gp130, which was affinity receptor for OSM (Gearing et al., 1992a; Liu
originally characterized as the signal transducer sub- et al., 1992b). Thus, while gp130 is the (cid:12) affinity-
unit within the high-affinity IL-6 receptor complex. converting receptor subunit for the high-affinity
receptor complexes for LIF, IL-6 and other members
of the IL-6 family of cytokines, it is the (cid:11) receptor
BACKGROUND subunitforOSMwithinthehigh-affinityOSMrecep-
torcomplex,and,inthiscontext,willbereferredtoas
Discovery OSMR(cid:11)(gp130).
Previous studies noted the presence of a high-
affinity receptor which was specific to OSM and did
High- and low-affinity receptors for oncostatin M
not bind LIF (Bruce et al., 1992b). While the shared
were originally detected using binding assays on a
LIF/OSM receptor described above is composed of
wide variety of cell types (Linsley et al., 1989; Horn
OSMR(cid:11)(gp130) and LIFR(cid:11), the OSM-specific
et al., 1990). Crosslinking studies using 125I-labeled
receptor is composed of OSMR(cid:11)(gp130) and a pre-
OSM revealed a major binding protein of approxi-
viously undescribed receptor subunit closely related
mately 160kDa (Linsley et al., 1989). The nature and
to OSMR(cid:11)(gp130), LIFR(cid:11), and other members of
identity of these receptors first came to light after the
the cytokine receptor family. This receptor subunit
discoverythatOSMwasstructurallyandfunctionally
converted the receptor binding of OSM to high
related to leukemia-inhibitory factor (LIF) Rose and
affinityintheabsenceofLIFR(cid:11)andwasthustermed
Bruce, 1991), and that OSM shared with LIF the
the OSM(cid:12) receptor (OSMR(cid:12)) (Mosley et al., 1996).
ability to bind the high-affinity LIF receptor (Bruce
An importantnoteis thatstudiesinmicehaveshown
et al., 1992a; Gearing et al., 1992a). The high-affinity
thatmurineOSMbindsonlytheOSM-specificrecep-
LIF receptor is a heterodimeric complex of two
tor with high affinity, as discussed further below.
receptor subunits, the LIF(cid:11) receptor (LIFR(cid:11)) which
binds LIF directly at low affinity (Gearing et al.,
1991) and gp130, a molecule previously shown to be
Alternative names
thesignalingsubunitofthehigh-affinityinterleukin6
(IL-6)receptorcomplex(Hibietal.,1990).Molecular
characterizationofLIFR(cid:11)andgp130revealedaclose The low-affinity OSM(cid:11) receptor gp130, herein
similarity between the two and to the members of a designated as OSMR(cid:11)(gp130), has also been called
newly described cytokine receptor family which the IL-6 signal transducer or the IL-6 receptor (cid:12)
1792 Timothy M. Rose and A. Gregory Bruce
chain (Hibi et al., 1990). The LIF (cid:11) receptor, which murine OSM directly at low affinity (Lindberg et al.,
actsasa(cid:12)affinity-convertingreceptorsubunitforthe 1998).However,themurinehomologofgp130,which
LIF/OSM shared receptor in humans, is variously also binds OSM directly at low affinity, has not been
designated as LIFR, LIFR(cid:11), LIFR(cid:12), or differentia- termed as such in the literature.
tion-stimulating factor receptor (Gearing et al., 1991;
Gearing et al., 1992b). The (cid:12) affinity-converting
Structure
receptorforthehigh-affinityOSM-specificreceptoris
termed OSMR(cid:12) or OSM receptor (cid:12) subunit in
humans (Mosley et al., 1996). In the murine system, Molecular cloning studies of OSMR(cid:11)(gp130),
only one high-affinity receptor complex exists for OSMR(cid:12), and LIFR(cid:11)have demonstrateda structural
murine OSM, which consists ofthe murine homologs relationship between the three receptor subunits
of OSMR(cid:11)(gp130) and OSMR(cid:12) (Ichihara et al., which categorizes them as members of the class I
1997;Lindbergetal.,1998).Bindingandcrosslinking cytokine receptor family (Mosley et al., 1996; Taga,
studiesinheterologouscellssuggestthatmurineOSM 1996; Lindberg et al., 1998). Members of this family
binds separately to both subunits of this receptor contain conserved hematopoietin domains of ap-
complex at low affinity, although the relative affini- proximately 200 amino acids in the extracellular por-
ties are unknown at this time. As such, the murine tion of the receptor (Bazan, 1990). Within this
homolog of OSMR(cid:12) is referred to as a specific domain are positioned four conserved cysteine
receptor for OSM to denote the fact that it binds residues and a WSXWS motif, where X is any
Table 1 OSMR(cid:11)(gp130), OSMR(cid:12), and LIFR(cid:11) gene sequences
Accession Species Source Type Size (bp) Reference
OSMR(cid:11)(gp130)
M57230 Human Placenta mRNA, complete 3085 Hibi et al., 1990
S80479 Human Embryo Alternate splice IF-1a 150 Sharkey et al., 1995
mRNA, partial
U58146 Human Blood cells Alternate splice IF-2a 153 Diamant et al., 1997
mRNA, partial
X62646 Mouse Macrophage mRNA, complete 2995 Saito et al., 1992
M92340 Rat Liver mRNA, complete 3053 Wang et al., 1992
OSMR(cid:12)
U60805 Human Placenta/bone mRNA composite, 4171 Mosley et al., 1996
marrow/fibroblast complete
AB015978 Mouse mRNA, complete 4026 Unpublished
AF058805 Mouse Skeletal muscle mRNA, complete 4792 Lindberg et al., 1998
LIFR(cid:11)
X61615 Human Placenta mRNA, complete 3591 Gearing et al., 1991
U78628 Human Placenta Alternate 50 224 Unpublished
noncoding exon
Not deposited Human Liver 3 alternate spliced Tomida, 1997
isoforms
U78104 Human Placenta Promoter and 4935 Unpublished
partial exon 1
S83362 Human Placenta 50 region and exon 1 1350 Tomida and Gotoh, 1996
AF018079 Human Alternate promoter 681 Unpublished
(nonplacental)
aIF=isoformdesignationusedwithinthischapter.
OSM Receptor 1793
amino acid. Additionally, three fibronectin type III In addition, alternately spliced mRNAs have been
modules which are considered to function as ligand- detected for OSMR(cid:11)(gp130) and LIFR(cid:11) (Table 1)
binding pockets are positioned proximal to the which produce different translated products that
transmembrane-spanning domain. correspond to soluble forms of the receptor subunits
(Figure 4 and Figure 5). An alternate splice of a 50
noncoding exon of the human LIFR(cid:11) has also been
Main activities and identified (Table 1). The gene for human LIFR(cid:11)
spans more than 70 kilobases and contains 20 exons
pathophysiological roles
(Tomida and Gotoh, 1996).
OSM is a pleiotropic cytokine which regulates cell
growth and differentiation in a wide variety of bio-
PROTEIN
logical systems, including hematopoiesis, neurogen-
esis, and osteogenesis (Bruce et al., 1992b). However,
theelaborationofthebiologicalactivitiesofOSMhas Accession numbers
been confounded by the presence of different OSM
receptor signaling systems in humans and mice. See Table 2.
In humans, OSM signals through two different
receptors complexes: the LIF/OSM shared receptor
(GearingandBruce,1992),whichshareshigh-affinity Description of protein
binding with LIF, an evolutionarily related protein
with structural similarity to OSM (Rose and Bruce,
A general comparison of the different OSM
1991; Rose et al., 1993), and the OSM-specific
membrane-bound receptor subunits encoded by the
receptor, which binds OSM uniquely (Bruce et al.,
mRNAs for OSMR(cid:11)(gp130) (Figure 1), OSMR(cid:12)
1992a). In mice, OSM signals only through the
(Figure2),andLIFR(cid:11)(Figure3)isshowninFigure6
murine homolog of the OSM-specific receptor
and Table 3. All contain three fibronectin type III
(Ichihara et al., 1997; Lindberg et al., 1998).
repeats proximal to a hydrophobic transmembrane
To confusematters,humanOSM, usedhistorically
domain. In addition, all have a hydrophobic signal
for in vitro and in vivo studies in mice, binds uniquely
sequence at the N-terminus and a C-terminal cyto-
tothemurineLIFreceptorandthusexhibitsonlythe
plasmic domain (200–300 amino acids). Conserved
biological activities of LIF in mice and not those of
hematopoietin domains ((cid:24)200 amino acids) contain-
OSM (Ichihara et al., 1997; Lindberg et al., 1998).
ing four positionally conserved cysteine residues in
Therefore, the biological activities for OSM are
the N-terminal region and a WSXWS motif in the C-
derived from signaling through two different recep-
terminal region are found in all three receptor
tors and overlap those of LIF in human but not
subunits. OSMR(cid:12) and LIFR have additional variant
murinesystems.ReceptorutilizationofOSMinother
hematopoietin domains, with a domain lacking the
species has not yet been well defined. As such, the
N-terminal cysteine residues in OSMR(cid:12) and a
literature on OSM should be reviewed with careful
domain lacking one pair of conserved cysteine
consideration of these findings.
residues in LIFR(cid:11). In the C-terminal cytoplasmic
domain of each receptor subunit are conserved
sequences corresponding to the box 1, box 2, and
GENE box 3 motifs involved in signal transduction
(Murakami et al., 1991; Baumann et al., 1994).
Accession numbers
Relevant homologies and species
See Table 1.
differences
Sequence
OSMR(cid:11)(gp130), OSMR(cid:12), and LIFR(cid:11) are related to
each other and to other members of the hematopoie-
The complete mRNA coding sequences for the tin receptor family. OSMR(cid:12) shares closest similarity
membrane-bound forms of human and mouse to the LIFR, with a 32% amino acid identity, while
OSMR(cid:11)(gp130), OSMR(cid:12), and LIFR(cid:11) have been OSMR(cid:11)(gp130) is less similar (Mosley et al., 1996).
determined(Figure1,Figure2,andFigure3;Table1). Structurally, OSMR(cid:12) and LIFR(cid:11) are very similar,
1794 Timothy M. Rose and A. Gregory Bruce
with the exception that the LIFR(cid:11) contains two since all other receptors have domains with both the
intact hematopoietin domains, whereas the OSMR(cid:12) conserved cysteine residues and the WSXWS motif.
has an N-terminal truncated domain lacking the OSMR(cid:11)(gp130) contains only one hematopoietin
conserved cysteine residues. OSMR(cid:12) is unique domain but contains an immunoglobulin (Ig)-like
among the hematopoietin receptors in this regard, domain at its N-terminus (Bazan, 1990).
Figure1 Nucleotideandencodedaminoacidsequenceofthetransmembrane
form of human OSMR(cid:11)(gp130). The hydrophobic signal sequence and
transmembrane-spanning domains are shown in bold and the WSXWS
hematopoietinmotifisboxed.Exonsplicejunctionsyieldingalternatelyspliced
mRNAs are indicated, using the exon numbering of the human LIFR(cid:11) gene
(Tomida and Gotoh, 1996).
OSM Receptor 1795
Figure 1 (Continued)
Comparison of the human and murine OSM domains with aWGNWS sequence in the N-terminal
receptor subunits demonstrates a close similarity truncated domain and a WSDWT motif in the
between the OSMR(cid:11)(gp130) (76% amino acid secondcompletedomain.WhereasthehumanLIFR(cid:11)
identity) and OSMR(cid:12) (55% amino acid identity) forms part of the LIF/OSM shared receptor complex
homologs (Lindberg et al., 1998). Although the withOSMR(cid:11)(gp130),themurinehomologofLIFR(cid:11)
mouse OSMR(cid:12) has the same structural domains as does not participate in binding or signaling of mouse
the human protein, it contains variant sequences OSM (Ichihara et al., 1997; Lindberg et al., 1998).
in the WSXWS motifs present in the hematopoietin Many studies examining the biological function of
1796 Timothy M. Rose and A. Gregory Bruce
Figure 1 (Continued)
OSM in mice have used human OSM which only et al., 1997), which is composed of the murine
mimics mouse LIF by binding and signaling homologsofOSMR(cid:11)(gp130)andOSMR(cid:12) (Lindberg
uniquely through the mouse LIF receptor complex et al., 1998).
(Ichihara et al., 1997; Lindberg et al., 1998).
Cell types and tissues expressing
Affinity for ligand(s) the receptor
A summary of low-affinity direct binding for indi- The OSMR(cid:11)(gp130) receptor is ubiquitously
vidual receptor subunits is shown in Table 4. Direct expressed on a wide variety of cell types and tissues
binding of OSMR(cid:11)(gp130) to OSM at low affinity (Saito et al., 1992). Distinctive patterns of expression
hasbeendetectedinboth humanandmurine systems havebeendemonstratedinthebrain(Watanabeetal.,
(Linsley et al., 1989; Ichihara et al., 1997; Lindberg 1996). Alternately spliced products are found in
et al., 1998). Although OSMR(cid:12) can bind OSM embryonic tissues (Sharkey et al., 1995) and in blood
directly in the murine system (low-affinity; Lindberg mononuclear cells (Diamant et al., 1997).
et al., 1998), no evidence for binding is seen in the OSMR(cid:12) receptor mRNA is detected in mouse
human system (Mosley, 1997). LIFR(cid:11) binds only heart, brain, spleen, lung, liver, skeletal muscle, and
LIF directly (low-affinity) and not OSM kidneytissue, butnotin testis (Lindberg et al., 1998).
(Gearing and Bruce, 1992). HumanLIFR(cid:11)isexpressedinavarietyofcelltissues,
A summary of binding to high-affinity receptor including the oocytes, preimplantation embryos and
complexesisshowninTable5.ThesharedLIF/OSM theplacenta(Gearingetal.,1991;Kojimaetal.,1995;
receptor complex composed of OSMR(cid:11)(gp130) van Eijk et al., 1996). Alternately spliced mRNAs
and LIFR(cid:11) binds both OSM and LIF with high encoding soluble human LIFR(cid:11) have been detected
affinity in humans (Gearing and Bruce, 1992; Bruce inliver,placenta,andchoriocarcinomacells(Tomida,
et al., 1992a). However, the murine homolog of the 1997). Studies on bone marrow stromal/osteoblastic
LIF/OSM receptor complex binds murine and cells have shown the presence of OSMR(cid:11)(gp130),
human LIF, as well as human OSM, but does not OSMR(cid:12), and LIFR(cid:11) (Bellido et al., 1996).
bind murine OSM (Ichihara et al., 1997). Therefore, A number of studies have determined sites of
in murine cells, human OSM mimics the activities expressionof mouse LIFR(cid:11)butthe exactcorrelation
of LIF and does not display the activities of murine with the human situation is not clear, since mouse
OSM. Murine OSM binds with high affinity only LIFR(cid:11),unlikehumanLIFR(cid:11),doesnotparticipatein
to the murine OSM-specific receptor (Ichihara OSM signaling. A comparison of the expression of
OSM Receptor 1797
the different human OSM receptor subunits, derived upstream of the transcriptional start site for LIFR(cid:11)
from Mosley et al. (1996) is shown in Table 6. has a consensus TATA motif 30bp upstream of the
initiation site and several potential regulatory
elements, including AP-2-, SP-1-, and NF-IL6-
Regulation of receptor expression
bindingsites(TomidaandGotoh,1996).Analternate
promoter in the LIFR(cid:11) gene with an upstream
Of the OSM receptor subunits, only the promoter enhancer which is active in placental tissues has also
regionforthehLIFR(cid:11)hasbeenreported.Theregion been characterized (Wang and Melmed, 1997).
Figure2 Nucleotideandencodedaminoacidsequenceofthetransmembrane
form of human OSMR(cid:12). The hydrophobic signal sequence and transmem-
brane-spanning domains are shown in bold and the WSXWS hematopoietin
motif is boxed.
1798 Timothy M. Rose and A. Gregory Bruce
Figure 2 (Continued)
Studies on lung-derived epithelial cells have shown (Sharkeyetal.,1995;Diamantetal.,1997)(Figure4).
that mRNA levels of OSMR(cid:11)(gp130) and OSMR(cid:12) In addition, alternately spliced mRNAs encoding
are upregulated by OSM (Cichy et al., 1998). three different soluble forms of human LIFR(cid:11) have
beendetectedinadultliver(Figure5)(Tomida,1997).
Release of soluble receptors Interestingly, some of the soluble forms encode new
cysteine residues in the C-terminal domain (Figure 4
Alternately spliced mRNAs encoding two different and Figure 5), suggesting the possibility of lipid
solubleformsofOSMR(cid:11)(gp130)havebeenidentified linkages to membranes, as is found with the receptor
OSM Receptor 1799
Figure 2 (Continued)
for ciliary neurotropic factor (CNTFR(cid:11)), which signaling. However, these molecules contain no
contains a glycosylphosphatidylinositol anchor at a intrinsic kinase activity and are dependent upon
C-terminal cysteine residue. Soluble forms of members of the JAK (Janus-activated kinase) family
OSMR(cid:11)(gp130) (50 and 100kDa) and LIFR(cid:11) have of constitutively associated kinases (JAK1, JAK2,
been detected in normal human serum, plasma, JAK3, TYK2) for phosphorylation and subsequent
and urine (Narzaki et al., 1993; Zhang et al., 1998). signal transduction (Stahl et al., 1994; reviewed in
Soluble murine OSMR(cid:11)(gp130) has been detected in Nakashima and Taga, 1998). Activation of the JAK
the ascitic fluid of tumor-bearing mice (Matsuda and kinases does not explain all downstream signaling
Hirano, 1994). events, and other pathways involving the Src family
tyrosine kinases, Ras, mitogen-activated protein ki-
nases (MAPK), phosphatidylinositol 3-kinase (PI-3
kinase) are also implicated in cytokine signaling
SIGNAL TRANSDUCTION
(Schiemann et al., 1997; reviewed in Hirano et al.,
1997). Signal transduction by OSM in endothelial
Associated or intrinsic kinases
cells has been shown to involve activation of the
p62yes tyrosine kinase (Schieven et al., 1992). Studies
The OSM receptor subunits OSMR(cid:11)(gp130), have suggested that the OSM-specific receptor
OSMR(cid:12), and LIFR(cid:11) all contain cytoplasmic signal transduction pathway utilizes the MAPK
domains with critical tyrosine residues involved in activation more than the LIF/OSM shared receptor
1800 Timothy M. Rose and A. Gregory Bruce
(Amaral et al., 1993; Thoma et al., 1994). OSM of a 250kDa protein is apparently a specific
activates Raf-1 which leads to the ultimate activa- consequence of OSM signaling through the OSM-
tion of MAPK. This requires the expression of specific receptor in A375 cells which involves the
STAT1 and is mediated through a JAK1-dependent JAK1, JAK2, and TYK2 tyrosine kinases (Auguste
pathway(Stancatoetal.,1997,1998).Phosphorylation et al., 1997).
Figure 3 Nucleotide and encoded amino acid sequence of the transmembrane
formofhumanLIFR(cid:11).Thehydrophobicsignalsequenceandtransmembrane-
spanning domains are shown in bold and the WSXWS hematopoietin motif is
boxed. Exon splice junctions yielding alternately spliced mRNAs are indicated,
using the exon numbering of the human LIFR(cid:11) gene (Tomida and Gotoh,
1996).