IL-9 Receptor

4 Pages·0.064 MB·English

by  Renauld J.-C.

IL-9 Receptor
Jean-Christophe Renauld*
Ludwig Institute for Cancer Research, Catholic University of Louvain, 74 Avenue Hippocrate,
Brussels, B-1200, Belgium
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.14004.
SUMMARY transduction but not for IL-9 binding, since an anti-
body directed against this molecule completely inhib-
itstheactivityofIL-9withoutaffectingtheK ofIL-9
High-affinity binding of IL-9 to target cells is medi- d
binding(Kimuraetal.,1995).Thefactthatthismole-
ated by a heterodimer consisting of the IL-9 receptor
cule, now called (cid:13)c, is shared by IL-2R, IL-4R, IL-
(cid:11) chain and the IL-2 receptor (cid:13) chain, also called (cid:13)c
7R,IL-9R,andIL-15Rcouldexplaintheoverlapping
(common(cid:13));bothchainsbelongtothehematopoietin
activities observed for these T cell growth factors.
receptor superfamily. The IL-9 receptor (cid:11) chain is
sufficient to confer high-affinity binding but both
chains are needed for signal transduction. The IL-9 Main activities and
receptor (cid:11) is associated with JAK1 tyrosine kinase, pathophysiological roles
and the IL-2 receptor (cid:13) chain with JAK3. Upon IL-9
binding, both kinases are activated and the IL-9
The IL-9R is believed to mediate all the biological
receptor(cid:13)isphosphorylatedonasingletyrosine.This
activities of IL-9 on T cells, B cells, mast cells, eosin-
phosphorylated residue is used as a docking site for
ophils, and hematopoietic progenitors, particularly
STAT1, STAT3, and STAT5 transcription factors.
for the development of asthma, for which a genetic
Activationofthesetranscriptionfactorsisconsidered
linkage has been reported (Holroyd et al., 1998).
to be critical for all IL-9 activities, because a mutant
on this single tyrosine residue completely lost its acti-
vity. The human IL-9R gene is located on the long GENE
arm pseudoautosomal region of the X and Y chro-
mosomes, a region which has been linked to asthma.
The human genome contains at least four IL-9R
pseudogenes with (cid:24)90% homology with the IL-9R
gene (Kermouni et al., 1995; Vermeesch et al., 1997).
BACKGROUND
Accession numbers
Discovery
Human IL-9R gene: L39064
ThemouseIL-9RcDNAwasidentifiedbyexpression
Human IL-9R pseudogenes: L39063, L39062
cloning in COS cells (Renauld et al., 1992).
The human IL-9 receptor cDNA was isolated by
Sequence
crosshybridization with a mouse probe (Renauld
et al., 1992).
ThemouseIL-9Rgeneiscomposedofnineexonsand
eight introns, sharing many characteristics with other
Structure
genes encoding cytokine receptors (Renauld et al.,
unpublished data).
The IL-9 receptor (IL-9R) was found to interact with The human IL-9R gene is composed of 11 exons
the (cid:13) chain of the IL-2R, which is required for signal and 10 introns, stretching over (cid:24)17kb.
1492 Jean-Christophe Renauld
A frequent alternative splicing of the human gene Description of protein
generatesanintriguingheterogeneityinthe50untrans-
lated region of the mRNA and introduces some
The murine IL-9R contains 468 amino acids, includ-
short open reading frames that might represent an
ing an extracellular domain, composed of 233 amino
additionallevelintheregulationofIL-9Rtranslation,
acids (Renauld et al., 1992) that shows the typical
as suggested for many genes involved in cell growth
features of the hematopoietin receptor superfamily,
(Kozak, 1991; Kermouni et al., 1995). More recently,
namely four conserved cysteines and a WSEWS
another splice variant was identified that contained
motif, located a few residues upstream from the
an in-frame deletion of a single residue of the extra-
transmembrane domain (Bazan, 1990). The human
cellular domain and lacked the ability to bind IL-9
IL-9R cDNA encodes a 522 amino acid protein.
(Grasso et al., 1998).
Analysisof the 50 flanking region revealed multiple
transcription initiation sites as well as potential bind-
Relevant homologies and species
ing motifs for AP-1, AP-2, AP-3, SP-1, and NF(cid:20)B,
although this region lacks a TATA box (Kermouni differences
et al., 1995).
Although the IL-9R pseudogenesare similar to the ThehumanIL-9R proteinshowsa53% identity with
IL-9R gene ((cid:24)90% identity), none of these copies the mouse IL-9R. The extracellular region is parti-
encodes a functional receptor: none of them contain cularly conserved with 67% identity, while the cyto-
sequences homologous to the 50 flanking region or plasmic domain is significantly larger in the human
exon 1 of the IL-9R gene and the remaining open receptor(231versus177residues)(Renauldetal.,1992).
readingframeshavebeeninactivatedbyvariouspoint The juxtamembrane region of the cytoplasmic tail
mutations and deletions (Kermouni et al., 1995). oftheIL-9RcontainsaPro-X-Prosequencepreceded
by a cluster of hydrophobic residues, which partially
fits a consensus motif shared by many cytokine
Chromosome location and linkages
receptors (IL-4R, IL-7R, IL-3R, EPOR, IL-2R(cid:12),
G-CSFR)(Murakamietal.,1991).Downstreamfrom
In the mouse, the IL-9R gene is a single copy gene this Pro-X-Pro motif, a striking homology was
located on chromosome 11 (Vermeesch et al., 1997). observed with the (cid:12) chain of the IL-2R and with the
The human IL-9R gene is located in the subtelo- erythropoietin receptor. As a result, for the first 33
meric region of chromosomes X and Y. IL-9R was amino acids of the cytoplasmic domain, a 40%
thus the first gene to be identified in the long arm identity was noticed between the human IL-9R and
pseudoautosomal region and turned out to be a the IL-2R(cid:12). This homologous region probably
unique tool to study this particular region of the explains why IL-9, like other cytokines such as IL-2,
genome. Using a polymorphism in the coding region induces JAK1 and JAK3 phosphorylation (Russell
of this gene, Vermeesch and colleagues showed that et al., 1994; Yin et al., 1994; Demoulin et al., 1996).
IL-9RisexpressedbothfromXandYandescapesX
inactivation (Vermeesch et al., 1997). Interestingly, a
genetic linkage has been reported between this region Affinity for ligand(s)
and asthma or bronchial hyperresponsiveness, suggest-
ing that different alleles of the IL-9R gene affect
A variety of mouse hematopoietic cells express high-
allergic responses (Holroyd et al., 1998).
affinityreceptorsforIL-9(K (cid:24)100pM)(Druezetal.,
d
The four IL-9R pseudogenes are located in the
1990). The (cid:13) chain of the IL-2R, which associates
subtelomeric regions of chromosomes 9q, 10p, 16p,
withtheIL-9R,isrequiredforsignaltransductionbut
and 18p (Kermouni et al., 1995).
notforIL-9high-affinitybinding(Kimuraetal.,1995).
Cell types and tissues expressing
PROTEIN
the receptor
Accession numbers
This issue has been poorly investigated so far. A
SwissProt: varietyofmousehematopoieticcells,includingTcells,
Mouse: Q01114 mast cells, and macrophages, express high-affinity
Human: Q01113 receptorsforIL-9(Druezetal.,1990).Morerecently,
IL-9 Receptor 1493
IL-9R was found to be expressed preferentially by JAK1activationrequirethesameregionoftheIL-9R
peritoneal B-1 lymphocytes. (Demoulin et al., unpublished data) and these two
molecules were shown to be associated in response to
Release of soluble receptors IL-9 (Yin et al., 1995). Taken together, these obser-
vations raise the possibility that, upon IL-9 activa-
tion, 4PS/IRS2 becomes phosphorylated by
Soluble receptors have never been reported at the
interacting directly with the JAK1 tyrosine kinase.
protein level. As observed for many members of the
After phosphorylation, 4PS/IRS2 binds the SH2
hematopoietin receptor superfamily, IL-9R mRNA
domain of various signaling proteins including the
has been identified that lack the sequences encoding
p85 subunit of the phosphatidylinositol 3-kinase
the transmembrane and cytoplasmic domains, as a
(Demoulin et al., unpublished data).
result of alternative splicing (Renauld et al., 1992).
However, the frequency of these mRNA seems quite
lowanditisnotyetclearwhethertheyreallyencodea
soluble IL-9-binding protein. DOWNSTREAM GENE
ACTIVATION
SIGNAL TRANSDUCTION
Transcription factors activated
Associated or intrinsic kinases
STAT1,STAT3,andSTAT5(Demoulinetal.,1996).
IL-9R interacts with the (cid:13) chain of the IL-2R, which
is required for signal transduction and is shared by
Genes induced
IL-2R, IL-4R, IL-7R, IL-9R, and IL-15R (Demoulin
and Renauld, 1998). So far, the only function of (cid:13)c
seems to recruit the tyrosine kinase JAK3, while IL- Granzyme A, granzyme B, mouse mast cell proteases
9RisassociatedwithJAK1.UponIL-9binding,both (MMCP), Ly6A/E, L-selectin, IL-6, adseverin
JAK1 and JAK3 become phosphorylated and cataly- (Robbens et al., 1998), Bcl-3 (Richard et al., 1999),
tically active. These kinases are likely to be respon- M-ras (Louahed et al., 1999).
sible for IL-9R phosphorylation on one of its five
tyrosine residues.
Promoter regions involved
Cytoplasmic signaling cascades
GAS site for Ly6A/E (Demoulin et al., 1999).
This single phosphorylated residue acts as a docking
site for STAT1, STAT3, and STAT5 – three trans-
cription factors that, after phosphorylation by the BIOLOGICAL CONSEQUENCES
JAK kinases associated to the receptor, form hetero-
OF ACTIVATING OR INHIBITING
orhomodimersandmigratetothenucleus(Demoulin
RECEPTOR AND
et al., 1996; Bauer et al., 1998).
IL-9 does not seem to induce or enhance the PATHOPHYSIOLOGY
phosphorylationoftheserine/threoninekinasesRaf-1
or MAP kinases in the Mo7E leukemia cell line Unique biological effects of
(Miyazawa et al., 1992), or in mouse lymphoid cells
activating the receptors
(Grasso et al., unpublished).
MoreclearlyestablishedistheactivationbyIL-9of
an adaptor protein called 4PS/IRS2, a feature shared See chapter on IL-9 activities.
with IL-4 signal transduction, where this pathway
was shown to be critical for growth regulation
(Keeganetal.,1994;Yinetal.,1995;Demoulinetal.,
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