IL-3 Receptor

John W. Schrader*
Department of Medicine, Biomedical Research Center, University of British Columbia,
2222 Health Science Mall, Vancouver, British Columbia, Canada V6T 1Z3
* corresponding author tel: 604-822-7810, fax: 604-822-7815, e-mail: john@brc.ubc.ca
DOI: 10.1006/rwcy.2000.20001.

SUMMARY common in the human, or either AIC2A or AIC2B in

the mouse, to generate a high-affinity IL-3 receptor.
The receptor for IL-3 is made up of two subunits,
both members of the cytokine receptor superfamily.
The smaller  subunit has a low affinity for IL-3 and Alternative names
the complex of IL-3 and the  subunit binds to the 
subunit to form a high-affinity signaling complex. AIC2A and AIC2B in the mouse refer respectively
The  subunit is shared with the receptors for GM- to the murine product of the duplicated  common
CSF and IL-5, hence its name,  common (c), and gene that binds IL-3 with low affinity, and the
alone, has no affinity for any of these three cytokines. ortholog of  common in the human which can
In the mouse, however, there is an additional, IL-3- interact with the  chains of the IL-3, GM-CSF or
specific  subunit, which is encoded by a duplication IL-5 receptors.
of the c gene and which has itself a low affinity for
IL-3. Signaling downstream of the receptor complex
involves activation of JAK2 kinase, tyrosine phos- Structure
phorylation of c and the initiation of signaling paths
regulating growth, survival, and differentiation. The three-dimensional structures of the  and 
subunits of the IL-3 receptor are not yet available. In
BACKGROUND
Discovery
The first IL-3-binding protein cloned was the murine
AIC2A protein (Itoh et al., 1990). This bound IL-3
with low affinity and was homologous with a closely
related molecule, AIC2B (Gorman et al., 1990).
AIC2A is the result of the recent duplication in the
mouse of the AIC2B gene, which is the murine
the case of both the  and  subunits, the deduced
protein sequences of the extracellular domains predict
structures that are homologous to those of other
receptors in this family, for which structures are
available such as the receptors for growth hormone,
prolactin, and erythropoietin.
Main activities and
pathophysiological roles
ortholog of the  common chain (c). c is shared The only known activity of the  unit of the IL-3
between the receptors for IL-3, GM-CSF, and IL-5 receptor is to bind IL-3. As noted above, the 
and interacts with complexes of GM-CSF, IL-3, or common chain is able to interact with complexes of
IL-5 with their respective low-affinity  subunits. The the IL-3, GM-CSF, and IL-5 receptors, each with
 subunit of the IL-3 receptor was subsequently their respective  subunits. There is no evidence that
discovered (Kitamura et al., 1991). It was shown to complexes of the IL-3 receptor  and  subunits exist
bind IL-3 with low affinity and then to interact with  in the absence of IL-3. In contrast, in the case of the
1900 John W. Schrader

related GM-CSF receptor, there is evidence that the  the characteristic distribution of cysteines, and the
and  subunits of the receptor are associated before WSXWS motif characteristic of receptors of the cyto-
the ligand binds. kine family. The cytoplasmic domain of the human
IL-3 receptor  subunit is relatively short and
contains no tyrosines (the murine ortholog has one)
GENE but does contain a proline-rich motif (`Box 1' motif)
characteristic of the cytoplasmic domain of receptors
Accession numbers of this family.
The extracellular domains of c (or AIC2A) again
Mouse  subunit: X64534 show the characteristic features of the members of the
Human  subunit: M74782 cytokine receptor family but are larger than that of
Human c receptor subunit: A39255 the  subunit as a result of a duplication of the basic
Mouse c receptor subunit: P26955 (AIC2B), cytokine receptor domain. The cytoplasmic domains
AAA39295 (AIC2A) of c or AIC2A have multiple tyrosines, many of
which have been shown by mutational studies to be
relevant to receptor function and to be phosphory-
Sequence lated following binding of IL-3.

The murine IL-3 receptor  subunit gene spans 10 kb

and includes 12 exons. The general genomic structure
is similar to that of other genes in the cytokine
Relevant homologies and species
receptor family, consistent with their common phy- differences
logenetic origin (Miyajima et al., 1995). The promoter
of the IL-3 receptor  subunit gene in the mouse has As noted only in the mouse, are there two  subunits
potential sites for GATA, Ets, c-myb, p1, and AP-2. of the IL-3 receptor, the additional  chain AIC2A
Chromosome location and linkages
In the mouse, the gene for the IL-3 receptor  subunit
is on chromosome 14, whereas that encoding the
corresponding  subunit for the GM-CSF receptor is
on chromosome 19. In the human, the genes for the 
subunits of both the IL-3 receptor and the GM-CSF
receptor are tightly linked and are on the pseudo-
autosomal regions of the X (Xp22.3) and Y (Yp11.3)
chromosomes.
having arisen by duplication of the c gene, and
evolved the capacity to itself bind IL-3.
Cell types and tissues expressing
the receptor
The IL-3 receptor  subunit is expressed on the broad
range of cells of hematopoietic origin upon which it is
alive. It is lacking on mature T and B lymphocytes
and neutrophils but present on most other nucleated
cells derived from the pluripotential hematopoietic
stem cells. There is some evidence for expression of
PROTEIN the IL-3 receptor on endothelial cells. The c subunit
is expressed more widely, being also present on
Accession numbers neutrophils.

Mouse  subunit: X64534

Human  subunit: M74782 Regulation of receptor expression
Human c receptor subunit: A39255
Mouse c receptor subunit: P26955 (AIC2B),
AAA39295 (AIC2A)
Description of protein
The  subunit of the IL-3 receptor is a member of the
cytokine receptor family. Its deduced protein
sequence has 378 amino acids in the human and has
Binding of its ligand results in internalization and
downregulation of the levels of the IL-3 receptor on
the cell surface. There is some evidence for upregula-
tion of expression of mRNA encoding the IL-3
receptor  subunit by IL-3. A genetic mutation leads
to decreased expression of the IL-3 receptor  subunit
and thus diminished responses to IL-3 in certain
strains of mice (e.g. A/J) (Ichihara et al., 1995; Leslie
et al., 1996).

SIGNAL TRANSDUCTION
Associated or intrinsic kinases
JAK2 kinase appears to be associated with the active
ligand-bound complex of the IL-3 receptor  subunit
IL-3 Receptor 1901
Elk-1. IL-3 also activates members of the other two
families of the MAP kinase superfamily, the p38MAP
kinases, and the JNK/stress-activated kinases.
At the head of another pathway activated by phos-
phorylation of the activated IL-3 receptor complex is
the lipid kinase PI-3 kinase. The SH2 domains of the
p85 subunit of PI-3 kinase bind to phosphotyrosines
and c or AIC2A. There is some evidence suggesting on SHP2 and IRS2, another of the proteins that bind
that JAK2 kinase may associate constitutively with to the receptor complex via a PTB domain and
the c. The cytoplasmic domain of the IL-3 receptor
 subunit is absolutely required for IL-3-mediated
signaling and one hypothesis is that the cytoplasmic
domain of the IL-3 receptor  subunit is involved in
recruiting JAK kinase to the heterodimeric, ligand-
themselves become phosphorylated on tyrosine. This
approximation of PI-3 kinase with its lipid substrates
in the membrane results in increased levels of the
products of its action. These phospholipids in turn
activate the PH domains of two enzymes PDK1 and
induced complex of the  and  subunits. PDK2, which phosphorylate and activate two serine/
threonine protein kinases, PKB and p70 S6 kinase.
PI-3 kinase activity is absolutely required for IL-3-
Cytoplasmic signaling cascades induced increases in levels of c-Myc mRNA, but p70
S6 kinase activity is not, suggesting that PKB activity
An early event is activation of the JAK2 protein is required for IL-3-induced upregulation of c-Myc.
tyrosine kinase. As noted above, this may result from Also docking onto the activated IL-3 receptor
apposition of two JAK2 kinase molecules brought complex are molecules with counter-regulatory activ-
together by ligand-induced approximation of the  ity. These include the tyrosine phosphotase SHP2,
and  subunits. In keeping with this notion, there is and the lipid phosphatase SHIP1, which dephos-
evidence that the formation of simple heterodimers phorylates products of PI-3 kinase action.
of the cytoplasmic domains of the  and  subunits
is both sufficient and necessary for mitogenesis
(Orban et al., 1999). However, higher order com- DOWNSTREAM GENE
plexes involving multiple  chains may also be
formed. The cytoplasmic domain of c or AIC2A
have multiple tyrosines, many of which have been
shown by mutational studies to be relevant to
receptor function and to be phosphorylated following
binding of IL-3. These phosphotyrosine residues serve
as docking sites. The PTB domain of the adapter
protein Shc links the activated receptor via Grb2 to
ACTIVATION
Transcription factors activated
IL-3-induced activation of tyrosine kinases leads to
activation of STAT5a and STAT5b transcription
factors. These cytoplasmic factors dock onto phos-
the Ras exchange factor mSOS1. Another potential photyrosines on the  subunit and themselves become
link to the Ras pathway is provided by the binding to phosphorylated on tyrosine by JAK2 kinase. This
c via its SH2 domain of the tyrosine phosphatase results in dimerization and translocation to the nu-
SHP2, which itself becomes tyrosine phosphorylated cleus, where they bind promoters with GAS elements.
and serves as a further docking site for complexes of
Grb2 and mSOS1. The translocation of mSOS1 to the
membrane brings it into proximity with its substrates, BIOLOGICAL CONSEQUENCES
the small GTPases of the Ras family. IL-3 binding
results in activation of M-Ras, a 29 kDa relative of OF ACTIVATING OR INHIBITING
p21ras and probably also of p21ras, although this has RECEPTOR AND
not been demonstrated formally. PATHOPHYSIOLOGY
Activation of the Ras family leads to activation of
the MAP kinase family through cascades of serine/
threonine kinases. Activation of p21ras leads to
Unique biological effects of
activation of Raf-1, and in turn MEK1 and MEK2 activating the receptors
and then the ERK1 and ERK2 kinases. One of the
substrates of the ERK kinases is Stathmin, a protein There is little evidence for any unique biological
involved in regulation of the stability of microtubules. effects downstream of the IL-3 receptor. Many of its
Others include transcription factors such as c-Myc or best-studied effects, such as stimulation of growth
1902 John W. Schrader
and survival, involve paths activated by many recep-
tors such as the Ras/MAP kinases, PI-3 kinase, Bcl-2,
etc. STAT5 is also activated downstream of other
cytokine receptors (e.g. those for erythropoietin or
IL-2) and any unique effects are likely to result from
combinatorial and quantitative balances of signals
also involved in signaling from other receptors.
Phenotypes of receptor knockouts
and receptor overexpression mice
Ichihara, M., Hara, T., Takagi, M., Cho, L. C., Gorman, D. M.,
and Miyajima, A. (1995). Impaired interleukin-3 (IL-3)
response of the A/J mouse is caused by a branch point deletion
in the IL-3 receptor alpha subunit gene. EMBO J. 14, 939
950.
Itoh, N., Yonehara, S., Schreurs, J., Gorman, D. M.,
Maruyama, K., Ishii, A., Yahara, I., Arai, K., and
Miyajima, A. (1990). Cloning of an interleukin-3 receptor
gene: a member of a distinct receptor gene family. Science
247, 324327.
Kitamura, T., Sato, N., Arai, K., and Miyajima, A. (1991).
Expression cloning of the human IL-3 receptor cDNA reveals
a shared beta subunit for the human IL-3 and GM-CSF recep-
tors. Cell 66, 11651174.
Leslie, K. B., Jalbert, S., Orban, P., Welham, M., Duronio, V.,
The knockout of the c gene results in a phenotype
similar to that seen in the GM-CSF knockout.
References
Gorman, D. M., Itoh, N., Kitamura, T., Schreurs, J., Yonehara, S.,
Yahara, I., Arai, K., and Miyajima, A. (1990). Cloning and
expression of a gene encoding an interleukin 3 receptor-like
protein: identification of another member of the cytokine recep-
tor gene family. Proc. Natl Acad. Sci. USA 87, 54595463.
and Schrader, J. W. (1996). Genetic basis of hypo-responsive-
ness of A/J mice to interleukin-3. Blood 87, 31863194.
Miyajima, I., Levitt, L., Hara, T., Bedell, M. A., Copeland, N. G.,
Jenkins, N. A., and Miyajima, A. (1995). The murine interleu-
kin-3 receptor alpha subunit gene: chromosomal localization,
genomic structure, and promoter function. Blood 85, 1246
1253.
Orban, P. C., Levings, M. K., and Schrader, J. W. (1999).
Heterodimerization of the alpha and beta chains of the inter-
leukin-3 (IL-3) receptor is necessary and sufficient for IL-3-
induced mitogenesis. Blood 94, 16141622.