GM-CSF Receptor

10 Pages·2000·0.107 MB·English

by  Nicola N.

GM-CSF Receptor
Nicos A. Nicola
*
Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research,
P.O. Royal Melbourne Hospital, Parkville, Victoria 3050, Australia
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.20004.
SUMMARY and AIC2B) revealed that the human molecule
(KH97) did not bind GM-CSF by itself but could
generatehigh-affinitybindinginthepresenceofGM-
The GM-CSF receptor is expressed primarily on
CSFR(cid:11) (Hayashida et al., 1990). This chain, now
myeloid cells and consists of two separate subunits,
termed the common (cid:12) chain, was shown to be a
both of which belong to the type I cytokine receptor
shared affinity-converting chain for GM-CSF, IL-3
family. The (cid:11) subunit binds GM-CSF with high
and IL-5 receptors each of which contains a unique
specificity but low affinity while the (cid:12) chain is shared
ligand-specific (cid:11) chain (Kitamura et al., 1991;
withtheIL-3andIL-5receptorsandconvertseachof
Tavernier et al., 1991).
these low-affinity interactions into one of high
affinity. The (cid:11) chain has only a short cytoplasmic
tail which is nevertheless essential for intracellular
signaling but the longer cytoplasmic tail of the (cid:12)
chain appears to transmit most of the biological Alternative names
signals.Knownsignalingpathwaysincludeactivation
of the JAK2/STAT5 and MAP kinase pathways and
The GM-CSF receptor (cid:11) chain is also called CSF-
induction of cell survival, proliferation, and func-
2RA and, in the CD nomenclature, CDw116. The
tional activation.
common (cid:12) chain of this receptor was also known as
AIC2B in the mouse and as KH97 in human.
BACKGROUND
Structure
Discovery
The high-affinity GM-CSF receptor consists of a
TheGM-CSFreceptorwasfirstdefinedusingbinding ligand-specific,low-affinity(cid:11)chainandasharedhigh-
of radioactive GM-CSF to mouse and human bone affinity converting common (cid:12) chain. Although both
marrow cells and cell lines (Park et al., 1986a, 1986b; chains are required for intracellular signaling, most
Walker and Burgess, 1985). These studies revealed signalingmoleculeshavebeenmappedtothe(cid:12) chain.
receptorheterogeneitybydemonstratingtheexistence Both receptor chains belong to the hematopoietin or
ofbothhigh-andlow-affinitybindingsites.Aspecific cytokinetypeIreceptorfamilydefinedbythepresence
GM-CSF-bindingreceptorwas clonedfromahuman of an extracellular 200 amino acid motif called the
placental cDNA expression library in 1989 (Gearing hematopoietindomainorcytokinereceptorhomology
et al., 1989) and shown to constitute only the low- domain. This domain consists of two halves, each of
affinity binding site. It has subsequently been termed which is similar to a fibronectin type III repeat and
the GM-CSFR(cid:11) chain. Meanwhile, cloning of the contains seven (cid:12) strands. The stoichiometry of the
single human equivalent of mouse IL-3 receptor complexisstillunknownbutmayconsistoftwoeachof
subunits defined by inhibitory antibodies (AIC2A the(cid:11)and(cid:12)chains.
1936 Nicos A. Nicola
Main activities and PROTEIN
pathophysiological roles
Accession numbers
These are as shown for GM-CSF and, for the
Human (cid:11) chain: SwissProt P15509 and other
common(cid:12) chain,alsoasshownforIL-3andIL-5.In
isoforms TrEMBL O00207, Q16564, Q14431
one patient with pulmonary alveolar proteinosis, a
Mouse (cid:11) chain: TrEMBL Q00941
point mutation in the common (cid:12) chain gene (C to A
Human (cid:12) chain: SwissProt P32927
at nucleotide position 1135 leads to Pro602 to Thr
Mouse (cid:12) chain: SwissProt P26955
alteration) results in reduced expression and function
of the protein (Dirksen et al., 1997) and this
phenotype can also be created in mice with loss of Sequence
the common (cid:12) gene (Nishinakamura et al., 1995;
Robb et al., 1995).
See Figure 1.
GENE Description of protein
The GM-CSF receptor (cid:11) chain gene (CSF2RA) The human (cid:11) chain is a type I membrane
occursinthepseudoautosomalregionoftheXandY glycoprotein of 400 amino acids (including the leader
chromosomes at Xp22.32 in humans (Gough et al., sequence). The extracellular domain extends from
1990; Rappold et al., 1992) and on chromosome 19 amino acids 23 to 320 and consists of about 100
(51.00cM) in the mouse (Disteche et al., 1992). The amino acids preceding a 200 amino acid domain that
common (cid:12) chain gene (CSF2RB) is on chromosome isconserved inall typeI cytokinereceptorscalled the
22q12.2-13.1 in humans (Shen et al., 1992) and on cytokine receptor homology domain (CRHD). This
chromosome 15 in the mouse (Gorman et al., 1992). domaincontainstwoconserveddisulfidebonds(126–
In humans the GM-CSF and IL-3 receptor (cid:11) chains 136, 165–178) and the conserved WSXWS sequence
are closely linked (within 190kb) in the pseudoauto- (WSSWS in the (cid:11) chain) and is predicted to have the
somal regions of the X and Y chromosomes (Kremer structure of two seven (cid:12)-stranded fibronectin III
et al., 1993) and in the mouse the common (cid:12) chain modules separated by a hinge region. There are 11
and the IL-3-specific (cid:12) chain (AIC2A) are closely potentialN-glycosylationsites (ataminoacids46,54,
linked to each other and to c-sis (within 250kb) 99, 123, 135, 182, 195, 223, 229, 272, and 305) in the
(Gorman et al., 1992). The human (cid:11) chain gene extracellulardomainandtheseappeartobenecessary
consistsof13exonsspanningabout44kb(Nakagawa for obtaining the correct structure of the receptor for
et al., 1994) while the mouse (cid:12) chain gene consists of ligand binding (Ding et al., 1995; Shibuya et al.,
14exonsspanningabout28kb(Gormanetal.,1992). 1991). Glycosylation probably explains the difference
In both cases the intron/exon boundaries are well between the molecular mass of the native protein
conserved and suggest a common evolutionary origin (80kDa) and the predicted mass (44kDa). The short
for this entire class of receptors. cytoplasmic domain of 55 amino acids contains the
conserved box 1 and box 2 elements characteristic of
classIcytokinereceptors.Twoalternateformsofthis
Accession numbers
transmembrane receptor have been described to arise
from alternate splicing. In one the last 25 amino
GenBank: acids are replaced by the sequence EMGPQRHHR-
Human (cid:11) chain cDNA (main membrane form): CGWNLYPTPGPSPGSGSSPRLGSESSL (Crosier
X17648 (Gearing et al., 1989) et al., 1991) while in the other the last 85 amino
Human (cid:11) chain cDNA (minor membrane form): acids are replaced by the sequence DDHLGGIHP-
M64445 (Crosier et al., 1991), L29349 (Hu et al., RGRERLPRRGLDREGNYLRPRGCRNGMDIS-
1994) ASATRGNCFLDDAVNLYIIFYVFI (Hu et al.,
Human soluble forms (by alternate splicing): L29348 1994). Alternative splicing is also known to generate
(Hu et al., 1994), M73832 (Raines et al., 1991) several different soluble forms of the human GM-
Mouse (cid:11) chain: M85078 (Park et al., 1992) CSF receptor (cid:11) chain. In one, the last 130 amino
Human(cid:12)chaincDNA:M59941,M38275(Hayashida acids are replaced by the sequence VVLTTG-
et al., 1990) TSALCTFMCS (Hu et al., 1994) while in another
Mouse(cid:12) chaincDNA:M93429(Gormanetal.,1992) the last 83 amino acids are replaced by the sequence
GM-CSF Receptor 1937
Figure 1 Amino acid sequence for human GM-CSF receptor (cid:11) chain and (cid:12) chain.
Leader signal sequence is underlined. Transmembrane region is bold and underlined.
Human GM-CSF receptor a chain:
MLLLVTSLLL CELPHPAFLL IPEKSDLRTV APASSLNVRF DSRTMNLSWD CQENTTFSKC
FLTDKKNRVV EPRLSNNECS CTFREICLHE GVTFEVHVNT SQRGFQQKLL YPNSGREGTA
AQNFSCFTYN ADLMNCTWAR GPTAPRDVQY FLYIRNSKRR REIRCPYYIQ DSGTHVGCHL
DNLSGLTSRN YFLVNGTSRE IGIQFFDSLL DTKKIERFNP PSNVTVTCNT THCLVRWKQP
RTYQKLSYLD FQYQLDVHRK NTQPGTENLL INVSGDLENR YNFPSSEPRA KHSVKIRAAD
VRILNWSSWS EAIEFGSDDG NLGSVYIYVL LIVGTLVCGI VLGFLFKRFL RIQRLFPPVP
QIKDKLNDNH EVEDEIIWEE FTPEEGKGYR EEVLTVKEIT
Human GM-CSF receptor b chain:
MVLAQGLLSM ALLALCWERS LAGAEERIPL QTLRCYNDYT SHIRVRWADT QDAQRLVNVT
LIRRVNEDLL EPVSCDLSDD MPWSACPHPR CVPRRCVIPC QSFVVTDVDY FSFQPDRPLG
TRLTVTLTQH VQPPEPRDLQ ISTDQDHFLL TWSVALGSPQ SHWLSPGDLE FEVVYKRLQD
SWEDAAILLS NTSQATLGPE HLMPSSTYVA RVRTRLAPGS RLSGRPSKWS PEVCWDSQPG
DEAQPQNLEC FFDGAAVLSC SWEVRKEVAS SVSFGLFYKP SPDAGEEECS PVLREGLGSL
HTRHHCQIPV PDPATHGQYI VSVQPRRAEK HIKSSVNIQM APPSLNVTKD GDSYSLTWET
MKMRYEHIDH TFEIQYRKDT ATWKDSKTET LQNAHSMALP ALEPSTRYWA RVRVRTSRTC
YNGIWSEWSE ARSWDTESVL PMWVLALIVI FLRIAVLLAL RFCGIYGYRL RRKWEEKIPN
PSKSHLFQNG SAELWPPGSM SAFTSGSPPH QGPWGSRFPE LEGVFPVGFG DSEVSPLTIE
DPKHVCDPPS GPDTTPAASD LPTEQPPSPQ PGPPAASHTP EKQASSFDFN GPYLGPPHSR
SLPDILGQPE PPQEGGSQKS PPPGSLEYLC LPAGGQVQLV PLAQAMGPGQ AVEVERRPSQ
GAAGSPSKES GGGPAPPALG PRVGGQDQKD SPVAIPMSSG DTEDPGVASG YVSSADLVFT
PNSGASSVSL VPSLGLPSDQ TPSLCPGLAS GPPGAPGPVK SGFEGYVELP PIEGRSPRSP
RNNPVPPEAK SPVLNPCERP ADVSPTSPQP EGLLVLQQVG DYCFLPGLGP GPLSLRSKPS
SPGPGPEIKN LDQAFQVKKP PGQAVPQVPV IQLFKALKQQ DYLSLPPWEV NKPGEVC
LGYS-GCSRGFHRSKTN (Ashworth and Kraft, The stoichiometry of the signaling receptor com-
1990; Raines et al., 1991). plexisnotknownalthoughithasbeenproposedtobe
The human common (cid:12) chain (897 amino acids GM-CSF (cid:11) (cid:12) . There is some evidence that (cid:12)
2 2 2
including the leader sequence) is also a type I homodimers existprior toligand bindingbutbecome
membrane glycoprotein that belongs to the class I tyrosine phosphorylated only after association with
cytokine receptor family. However it contains two the complex of GM-CSF with the receptor (cid:11) chain
copies of the CRHD in the extracellular region (427 (Muto et al., 1996). On the other hand there is also
amino acids) and also displays a much longer evidence that (cid:11)/(cid:12)c heterodimers also pre-exist before
cytoplasmic domain (437 amino acids). It contains ligand association (Woodcock et al., 1997) and that
three potential N-glycosylation sites (positions 58, two(cid:11)chainsarepresentinthereceptorcomplex(Lia
191, and 346) but appears to be more lightly et al., 1996). Finally, there is also some evidence that
glycosylated than the (cid:11) chain (Shibuya et al., 1991). GM-CSF-induced covalent disulfide bond formation
Thepredictedmolecularmassofthematureproteinis between (cid:11) and (cid:12) chains (involving Cys86 and Cys91
95kDaandtheobservedmolecularweightof120kDa in the latter) may be necessary for productive
suggests that some glycosylation does occur. signaling (Stomski et al., 1998).
By analogy with the site II binding site on the
growth hormone receptor, the binding site on the Relevant homologies and species
common (cid:12) chain ((cid:12)c) for GM-CSF (especially at
differences
Glu21)consistsofthepredictedB0-C0 andF0-G0 loops
ofthemembraneproximalhematopoietindomain.In
the former, His367 as well as Tyr365 and Ile368 are The overall structure of the GM-CSF receptor
the most critical residues (Lock et al., 1994; complex is the same in mice and humans. However,
Woodcock et al., 1994) while in the latter Tyr421 is there is no crossreactivity in the binding specificity of
critical (Woodcock et al., 1996). In the (cid:11) chain the two species. Nevertheless, it is known that the
Arg280 in the predicted F0-G0 loop of the hemato- mouse common (cid:12) chain can form an active signaling
poietin domain also appears to be critical for binding complex with the human GM-CSF receptor (cid:11) chain
GM-CSF, probably through a charge–charge inter- despiteitsinabilitytoconvertthelow-affinitybinding
action with Asp112 (Rajotte et al., 1997). reaction to one of high affinity. Consequently,
1938 Nicos A. Nicola
significantly higher concentrations of human GM- The (cid:12)c gene contains putative PU1- and GATA-1-
CSF are required for signaling in this artificial binding sites upstream of a conserved transcriptional
situation (Metcalf et al., 1990). initiationsitebutregulationofexpressionofthisgene
in mice and humans is poorly understood (Gorman
et al., 1992).
Affinity for ligand(s)
Release of soluble receptors
The human GM-CSF receptor (cid:11) chain binds GM-
CSF specifically but with a low-affinity equilibrium
dissociation constant(K ) of 1–5nMat 4(cid:14)C (Gearing Soluble forms of the (cid:11) chain arise from alternate
d splicing but little is known of the regulation of this
et al., 1989). Binding of GM-CSF to the common (cid:12)
process or secretion or in vivo half-lives.
chain is undetectable but the complex of (cid:11) and (cid:12)
chains binds GM-CSF with high affinity (K =10–
d
100pMat4(cid:14)C)(Hayashidaetal.,1990).Insomecells
SIGNAL TRANSDUCTION
intermediate affinity receptors have also been
described (K =300–800 pM) but these also appear
d Associated or intrinsic kinases
to be constituted from (cid:11) and (cid:12) chains (Wheadon
et al., 1997). Essentially identical results were
obtained for mouse GM-CSF receptors (Park et al., The GM-CSF receptor has no intrinsic tyrosine
1992; Walker and Burgess, 1985). kinase activity. The best-studied tyrosine kinase
associated with GM-CSF receptor signaling is the
cytoplasmic kinase JAK2. JAK2 binds to a proline-
Cell types and tissues expressing the rich sequence in (cid:12)c (box 1) proximal to the
transmembrane domain but does not appear to bind
receptor
to the (cid:11) chain (Quelle et al., 1994). Only the N-
terminal 290 amino acids but not the kinase or
In mice and humans GM-CSF receptors have been
kinase-likedomainsofJAK2arerequiredforbinding
detected on neutrophils, macrophages and eosino-
(Zhao et al., 1995). Despite the lack of binding to
phils and their precursors (DiPersio et al., 1988) as
JAK2, the cytoplasmic domain of the (cid:11) chain is
well as myeloid dendritic cells (Yamada et al., 1997).
necessary for JAK2 phosphorylation, activation, and
Therehavebeenconflictingreportsonwhetherornot
signaling (Doyle and Gasson, 1998). It may be that
functional GM-CSF receptors are expressed on
the (cid:11) chain cytoplasmic domain is necessary to
human endothelial cells (Bussolino et al., 1993;
aggregate (cid:12)c chains so that two JAK2 molecules can
Yong et al., 1991). The low-affinity (cid:11) chain of the
cross-activate each other or that the (cid:11) chain binds a
GM-CSF receptor has been detected in placental
distinct kinase needed for JAK2 activation. The
trophoblasts (Gearing et al., 1989; Hampson et al.,
importance of JAK2 kinase activity for most
1993).GM-CSFreceptorshavealsobeendetectedon
GM-CSF-dependent signaling functions has been
arange ofmyeloid cell lines, aswell ashematopoietic
demonstratedbyexperimentalmutationoftheJAK2-
and nonhematopoietic tumor cells (Baldwin et al.,
bindingsiteon(cid:12)corbytheuseofdominant-negative
1989;Hirschetal.,1995;Rokhlinetal.,1996;Crosier
formsofJAK2(Watanabeetal.,1996).Severalother
et al., 1997; Rivas et al., 1998).
cytoplasmic tyrosine kinases such as fps/fes, lyn, fyn,
yesandhckhavebeenshowntobeactivatedbyGM-
CSFsignalingandinsomecasestobeassociatedwith
Regulation of receptor expression
(cid:12)c or to be necessary for GM-CSF signaling events
(Corey et al., 1993; Hanazono et al., 1993; Linnekin
The (cid:11) chain gene contains binding sites for the ets- et al., 1994; Li and Chen, 1995; Li et al., 1995;
like transcription factor PU1 at nucleotides (cid:255)53 to Brizzi et al., 1996; Wei et al., 1996; Yousefi et al.,
(cid:255)41andstudiesinvitroandinvivo(inPU1knockout 1996; Park et al., 1998).
mice) have demonstrated an essential role for this
transcription factor in the induction of (cid:11) chain
Cytoplasmic signaling cascades
expression (Hohaus et al., 1995; Anderson et al.,
1998). In addition a C/EBP(cid:11)-binding CCAAT site at
nucleotides (cid:255)70 to (cid:255)54 is required for both positive Receptor activation leads to phosphorylation of (cid:12)c
andnegativetranscriptionalregulation(Hohausetal., cytoplasmic tyrosine residues and of cytoplasmic
1995). latent transcription factors STAT5a and STAT5b
GM-CSF Receptor 1939
(Mui et al., 1995). In one study neither GM-CSF- In terms of functional effects, the GM-CSF
dependent STAT5 phosphorylation nor proliferation receptor appears to consist of several discrete
weredependentonreceptortyrosinephosphorylation regions. Initiation of cell proliferation requires only
(Okuda et al., 1997) but in another study all tyrosine the membrane proximal region (box 1 and box 2) of
phosphorylation sites on the receptor were required (cid:12)c which correlates with activation of JAK2 and
for STAT5 phosphorylation and for optimal pro- transcriptional activation of myc and pim-1 (Sato
liferation(Itohetal.,1998).STAT5aisoformsappear etal.,1993;Watanabeetal.,1996;Smithetal.,1997).
to be preferentially activated by GM-CSF (Rosen Downstream regions up to residue 643 of the mature
et al., 1996) and gene deletion studies of STAT5a in proteinarerequiredforlong-termcellsurvivalevenin
mice suggested that this isoform is most critical for a the presence of serum (Inhorn et al., 1995; Kinoshita
full proliferative response to GM-CSF (Feldman etal.,1995;Smithetal.,1997;Chaoetal.,1998)while
et al., 1997). After phosphorylation, STAT5 proteins further downstream regions including tyrosine 750
form homo- or heterodimers (STAT5a:5a, (mature protein) and Ras activation enhance cell
STAT5a:5b) by binding of the SH2 domain of one survivalbutarenotrequiredinthepresenceofserum
STAT molecule to the tyrosine phosphate site of (Inhorn et al., 1995; Kinoshita et al., 1995).
another. They are then translocated to the nucleus Paradoxically, residues up to 643 were also required
and activate transcription of genes with STAT- for clonal suppression accompanying cell differentia-
response elements (see below). tion in myeloidleukemia cell lines, whiledownstream
A second link to transcriptional activation is regions to residue 799 were required for the full
through activation of the Ras/MAP kinase pathway. spectrumofthedifferentiatedphenotype(Smithetal.,
This occurs through binding of the PTB domain of 1997; Matsuguchi et al., 1998). Finally, the region
the adapter protein SHC to phosphorylated tyrosine between residues 799 and the C-terminus negatively
577 (numbering from the mature protein) or 593 regulates proliferative signaling by the GM-CSF
(numbering from the initiating methionine) on the (cid:12)c receptor (Smith et al., 1997).
cytoplasmic domain (Pratt et al., 1996; Okuda et al., The (cid:11) chain cytoplasmic domain is required for all
1997). SHC becomes tyrosine phosphorylated and aspects of GM-CSF signaling, presumably by
binds to GRB2, which in turn associates with initiating tyrosine phosphorylation and activation of
membrane-associated SOS, a guanine nucleotide (cid:12)c (Muto et al., 1995; Doyle and Gasson, 1998).
exchanger that activates the small GTPase Ras. Ras However, if (cid:12)c cytoplasmic domains are artificially
activatesthecytoplasmicserine/threoninekinaseRaf- dimerized in the absence of (cid:11) chain cytoplasmic
1 which in turn sets up a serine/threonine kinase domains by the use of chimeric receptors, signaling is
cascade through MEK and MAP kinase that intact so the role of the (cid:11) chain appears to be to
ultimately phosphorylates and activates nuclear activate the signaling capacity of (cid:12)c (Muto et al.,
transcription factors that induce fos expression. 1995;Pateletal.,1996).Ithasbeensuggestedthatthe
GM-CSF also activates jun kinase (JNK) activation (cid:11) chain alone is sufficient to signal GM-CSF-
throughaprocessthatinvolvesboththebox1region mediated increases in glucose transport (Ding et al.,
and multiple tyrosine residues in the cytoplasmic 1994)butthiscouldnotbeachievedincellsfrommice
domain of (cid:12)c (Liu et al., 1997). which express only the (cid:11) chain (Scott et al., 1998).
The tyrosine phosphatase SHP-2 binds to any of
three phosphotyrosine residues on activated (cid:12)c (577,
612, 695 mature protein or 593, 628, 712 full-length
protein)(Okudaetal., 1997;Itohet al.,1998)butthe
consequences of activating SHP-2 are unknown. DOWNSTREAM GENE
SHP-1alsobindsto(cid:12)c,althoughthesiteisunknown,
ACTIVATION
anditappearstoactasanegativeregulatoratleastof
proliferative signaling since moth-eaten mouse
Transcription factors activated
macrophages (which lack SHP1 activity) are hyperre-
sponsive to GM-CSF (Jiao et al., 1997).
GM-CSF action leads to tyrosine phosphorylation GM-CSFinducesfosandjuncomponentsoftheAP-
of phosphatidylinositol 3-kinase and activation of its 1orserumresponsetranscriptionalcomplexes.Italso
activity (conversion of PI(4,5)P to PI(3,4,5)P ). induces phosphorylation and activation of STAT5a
2 3
Distal regions of (cid:12)c (residues 626–763 of the mature and STAT5b with occasional reports of activation of
protein)arerequiredforthebindingandactivationof STAT1andSTAT3.GM-CSFalsoinducestranscrip-
this kinase (Corey et al., 1993; Sato et al., 1993; tional activity of E2F probably by dissociation of the
Jucker and Feldman, 1996). p107 inhibitor.
1940 Nicos A. Nicola
Genes induced Phenotypes of receptor knockouts
and receptor overexpression mice
GM-CSFinducestranscriptionoftheAP-1transcrip-
tion factors fos (Sato et al., 1993; Watanabe
Mice in which the (cid:12)c gene has been deleted have a
et al., 1993) and jun (Liu et al., 1997) in most cell
phenotypeexpectedforacombinedGM-CSFandIL-
typesthatdisplayGM-CSFreceptors, Fcreceptor (cid:13)1
5knockoutwithnoeffectonIL-3functionbecauseof
(Rosen et al., 1996), fms (the M-CSF receptor)
the existence of an alternate IL-3-specific (cid:12) chain.
(Helftenbein et al., 1996), and scavenger receptor A
Thus the mice display lymphoid infiltration in the
(SRA)(Guidezetal.,1998)inmacrophages,andmcl-
lungs with a pulmonary alveolar proteinosis-like
1 and A1 (pro-survival bcl-2-related genes) (Chao
disease in which surfactant is not cleared and
et al., 1998; Feldman et al., 1997), early growth
accumulates in the alveoli. In addition, eosinophil
response 1 gene (egr-1) (Watanabe et al., 1997), myc
numbers in the blood and bone marrow are very low
andpim-1(Satoetal.,1993;Watanabeetal.,1995)in
andthemicefailtomountaneosinophilicresponseto
myeloid progenitor cells. GM-CSF also induces
parasitic infections (Nishinakamura et al., 1995;
expression of a family of negative regulators of
Robb et al., 1995). There are no reports of the
cytokine signaling including CIS, SOCS-1, SOCS-2,
phenotype of GM-CSF receptor (cid:11) chain knockouts.
and SOCS-3 (Yoshimura et al., 1995; Starr et al.,
TransgenicmiceengineeredtoexpresshumanGM-
1997).
CSF receptor (cid:11) and (cid:12) chains off constitutive
promoters showed that progenitor cells from most
Promoter regions involved
hematopoietic lineages (including erythroid cells,
megakaryocytes, mast cells, blast cells, and NK
Induction of myc and pim-1 gene expression by GM- cells) responded to human GM-CSF with prolifera-
CSF requires only the box 1 region of the receptor tion and differentiation. This suggested that the
althoughdownstreamregionsenhancethisinduction. hematopoietic specificity of GM-CSF is determined
The cis-acting P2 promoter region of the myc gene by where receptors are expressed rather than by the
appears to mediate the induction and the effect of signaling capacity of the receptor itself (Nishijima
GM-CSF is somehow to allow dissociation of p107 etal.,1995,1997b).InjectionofhumanGM-CSFinto
(a pocket protein transcriptional inhibitor) from the these mice resulted in multilineage proliferation,
E2Ftranscriptionalactivator(Watanabeetal.,1995). depletion of the bone marrow and expansion of
Inductionoffosandegr-1geneexpressionrequires extramedullary hematopoiesis in the spleen and liver.
the concerted action of both the MAP kinase and The thymus, however, was shrunken and although
STAT pathways acting on the serum response GM-CSF stimulated proliferation of most T cell
element (SRE) and STAT-inducible elements (SIE), subsets it inhibited the formation and failed to
respectively (Watanabe et al., 1997). stimulate the proliferation of CD4+CD8+ T cells
Inductionofthemcl-1genebyGM-CSFrequiresa (Nishijima et al., 1997a; Yasuda et al., 1997).
regionbetween(cid:255)197to(cid:255)69(Chaoetal.,1998)while
induction of the SRA gene requires an enhancer
about 4kb upstream of the initiation site (Guidez Human abnormalities
et al., 1998).
Defective expression or mutation of (cid:12)c has been
BIOLOGICAL CONSEQUENCES associated with some cases of pulmonary alveolar
proteinosis (PAP) (Dirksen et al., 1997). It has also
OF ACTIVATING OR INHIBITING
been reported that some pediatric patients with acute
RECEPTOR AND
myeloid leukemia associated with respiratory distress
PATHOPHYSIOLOGY or pulmonary alveolar proteinosis-like disease have
defectiveexpressionof(cid:12)candofthe(cid:11)chain(Dirksen
Unique biological effects of et al., 1998). While some experimental mutations of
(cid:12)c have been shown to lead to myelodysplasia
activating the receptors
(Jenkins et al., 1995, 1998; McCormack and Gonda,
1997), analyses of leukemia patients have generally
The unique activities are those associated with GM- failedtorevealanymutationsinthe(cid:11)or(cid:12)cchainsof
CSF and include the maintenance of surfactant the GM-CSF receptor (Brown et al., 1994; Wagner
clearance from the lung as well as resistance to some etal.,1994;Deckeretal.,1995;Freeburnetal.,1996,
infections. 1997, 1998).
GM-CSF Receptor 1941
THERAPEUTIC UTILITY Crosier,K.E.,Wong,G.G.,Mathey-Prevot,B.,Nathan,D.G.,
and Sieff, C. A. (1991). A functional isoform of the human
granulocyte/macrophage colony-stimulating factor receptor
Effect of treatment with soluble
has an unusual cytoplasmic domain. Proc. Natl Acad. Sci.
USA88,7744–7748.
receptor domain
Crosier,K.E.,Hall,L.R.,Vitas,M.R.,andCrosier,P.S.(1997).
Expression and functional analysis of two isoforms of the
The soluble (cid:11) and (cid:12) chains are expected to be humanGM-CSFreceptoralphachaininmyeloiddevelopment
inhibitors of GM-CSF action but no therapeutic andleukaemia.Br.J.Haematol.98,540–548.
studies have yet been performed. Decker, J., Fiedler, W., Samalecos, A., and Hossfeld, D. K.
(1995).Absenceofpointmutationsintheextracellulardomain
of the alpha subunit of the GM-CSF receptor in a series of
Effects of inhibitors (antibodies) to patients with acute myeloid leukemia (AML). Leukemia 9,
185–188.
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