Hematopoietic Receptor Family

8 Pages·2000·0.088 MB·English

by  Miyajima A.

Hematopoietic Receptor
Family
Atsushi Miyajima*
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Tokyo,
Bunkyo-Ku, 113-0032, Japan
*corresponding author tel:[phone], fax:[phone],
e-mail: [email protected]
DOI: 10.1006/rwcy.2000.02010.
SUMMARY mechanism to overcome any defect in the three
cytokines.
The functional high-affinity receptors for IL-3, IL-5,
INTRODUCTION
and GM-CSF are heterodimeric receptors consisting
of a cytokine-specific (cid:11) subunit and the common (cid:12)
subunit, (cid:12)c, which is shared by the three cytokines. IL-3, IL-5, and GM-CSF are related to each other
In the mouse, the IL-3-specific (cid:12) subunit, homol- genetically, structurally, and functionally, and stimu-
IL3
ogous to (cid:12)c, is present and forms a high-affinity late development of hematopoietic cells. IL-3 and
receptor only with the IL-3R(cid:11). These subunits are GM-CSFactonabroadrangeofhematopoieticpro-
members of the type I cytokine receptor family. genitors and thereby exhibit a number of different
Asthe(cid:12)subunitsplayamajorroleinsignaling,the biological activities, whereas IL-5-responsive cells are
threecytokinesexhibitsimilarbiologicalfunctionson restricted to eosinophils, basophils, and some mouse
the same target cells. The JAK2 tyrosine kinase is B cells. IL-3, GM-CSF, and IL-5 exhibit almost
associatedwithboth(cid:12) subunitsandisactivatedupon identical biological activities when they act on the
cytokinestimulation.Themembrane-proximalregion same target cells such as eosinophilic progenitors.
of (cid:12)c is responsible for the activation of JAK2 and These cytokines are mainly produced by activated
STAT5 as well as induction of c-myc. The signals T cells and mast cells, but the production by bone
induced by this region are required for cell cycle pro- marrow stroma cells is minimal. Thus, it has been
gression and DNA synthesis. The activation of the hypothesizedthatthesecytokinesplayamajorrolein
Ras pathway requires the distal region of (cid:12)c and is hematopoiesis in an emergency situation such as
involved in suppression of apoptosis. As IL-3, IL-5, inflammation (Arai et al., 1990).
and GM-CSF are produced mainly from activated T The common activities of the three cytokines are
cells and mast cells, it has been hypothesized that now explained by the structures of the receptors. The
these cytokines play a major role in inductive hema- receptors for IL-3, IL-5, and GM-CSF are composed
topoiesis associated with immune and inflammatory of a cytokine-specific (cid:11) subunit and a common (cid:12)
reactions. However, mice lacking the entire functions subunit,(cid:12)c(Miyajimaetal.,1993).Asthe(cid:12)csubunit
of IL-3, IL-5, and GM-CSF are viable and no sig- plays a critical role in signal transduction, similar
nificant defects other than a reduced level of eosino- signalsaretransmittedthroughthe(cid:12) subunit,andthe
phils and some defects in mast cell development were (cid:11)subunitsprovidespecificitytocytokines.Thischap-
found, even in mice infected with bacteria and ter describes the structure, expression, and functions
parasites. Thus, there appears to be a compensatory of the IL-3, IL-5, and GM-CSF receptors.
1892 Atsushi Miyajima
STRUCTURE OF THE IL-3, IL-5, genes are colocalized in the human pseudoautosomal
region of the sex chromosomes (Gough et al., 1990),
AND GM-CSF RECEPTORS
whereas the IL-5R(cid:11) gene is on human chromosome
3p25–p26 (Isobe et al., 1992).
The high-affinity receptors for IL-3, GM-CSF, and In the mouse, there are two homologous (cid:12) sub-
IL-5consistofacytokine-specific(cid:11)subunitandacom- units:(cid:12)c(alsoknownasAIC2B)andtheIL-3-specific
mon (cid:12) subunit, (cid:12)c (Miyajima et al., 1993) (Figure 1). (cid:12) subunit, (cid:12) (also known as AIC2A) (Itoh et al.,
IL3
Both are members of the class I cytokine receptor 1990; Gorman et al., 1990), which binds IL-3 with
superfamily. The (cid:11) subunits are glycoproteins of 60– low affinity and forms a high-affinity receptor with
70kDa with a small cytoplasmic domain of about 50 IL-3R(cid:11) only (Hara and Miyajima, 1992) (Figure 1).
amino acid residues and bind their specific ligand No functional differences have been found between
with low affinity. The shared (cid:12)c is a glycoprotein of the two high-affinity mIL-3Rs which consist of either
120–130kDawithtworepeatsofaconservedmotifof (cid:12)cor(cid:12) .Thetwo(cid:12) subunitgenesaretightlylinked
IL3
the class I cytokine receptors in the extracellular on mouse chromosome 15 (Gorman et al., 1992)
domain. Its large cytoplasmic domain contains two and are placed in a head-to-head configuration
motifs known as Box-1 and Box-2 which are con- (Hannemann et al., 1995). The human (cid:12)c gene is on
served in members of the class I cytokine receptors. chromosome 22q12.2–13.1 (Shen et al., 1992) and
The (cid:12)c does not bind any cytokine by itself, but is there is no evidence that (cid:12) exists in the human.
IL3
required for the formation of a high-affinity recep- Like receptor tyrosine kinases, multimerization
tor with any of the three (cid:11) subunits, IL-3 receptor (cid:11) of the receptor subunits is a key step for activation
(IL-3R(cid:11)), GM-CSF receptor (cid:11) (GM-CSFR(cid:11)), and of the class I cytokine receptors. Although the
IL-5 receptor (cid:11) (IL-5R(cid:11)). IL-3R(cid:11) and GM-CSFR(cid:11) cytoplasmic domains of both (cid:11) and (cid:12)c are required
Figure 1 Receptors for IL-3, GM-CSF, and IL-5. The high-affinity receptors for IL-3,
GM-CSF,and IL-5consist ofa cytokine-specific (cid:11) subunit andthe common (cid:12) subunit,
(cid:12)c. There is the IL-3-specific (cid:12) subunit (cid:12) in the mouse but not in the human.
IL3
mIL-3R IL-3R GM-CSFR IL-5R
IL3Ra IL3Ra GMRa IL5Ra
b b b b
IL3 c c c
Hematopoietic Receptor Family 1893
for signaling, the (cid:12)c cytoplasmic domain plays a also found in nonhematopoietic tissues such as
major role in signal transduction. This is supported testis, placenta, and brain (Morikawa et al., 1996;
by experiments using chimeric receptors that are Korpelainen et al., 1993; Gearing et al., 1989). (cid:12)c
forced to form a dimer, e.g. the chimeric receptor and (cid:12) are expressed in various myeloid progenitor
IL3
which consists of the (cid:12)c cytoplasmic domain and the cells, macrophages, mast cells, CD5-positive B cells,
extracellular domain of homodimerizing EPOR and some endothelial cells, but not in erythroblasts,
induced full growth signals in response to EPO mature T cells, and fibroblasts(Gorman et al., 1990).
(Sakamaki et al., 1993), whereas similar chimeric Expression of the (cid:11) subunits is more restricted to
receptors with a cytoplasmic domain of the (cid:11) cytokine-responsive cells: IL-3R(cid:11), but not GM-
subunits failed to induce any signals (Eder et al., CSFR(cid:11) and IL-5R(cid:11), is expressed in mast cells and
1994;Mutoet al.,1995).Thusthe(cid:11)subunitsprovide multipotential progenitor cells that form the CFU
the cytokine specificity and (cid:12)c induces common mix. In contrast, IL-5R(cid:11) is predominantly expressed
signals. This model clearly explains the functional in eosinophils and a subset of B cells, and IL-5 is a
overlap between the three cytokines. major cytokine for eosinophils, but not for other
Alanine substitution mutagenesis of (cid:12)c identified hematopoietic cells (Takatsu et al., 1994).
the amino acid residues of (cid:12)c (Y365–I368) essential IL-3 and GM-CSF exhibit a broad spectrum of
for binding to GM-CSF (Woodcock et al., 1994). biological functions, while IL-5 function is restricted
Evidence was presented that the GM-CSF receptor to mainly eosinophils (Arai et al., 1990). The func-
exists as a preformed complex that can be activated tional differences between the three cytokines may
by GM-CSF, IL-3, and IL-5 (Woodcock et al., 1997) be due to the restricted expression of the (cid:11) subunits.
and the IL-3 and GM-CSF receptors undergo co- Alternatively, each (cid:11) subunit may play an active role
valent dimerization of the respective (cid:11) subunit with in inducing cytokine-specific functions. These pos-
(cid:12)cinthepresenceofcognatecytokine.Cys86,Cys91, sibilities were tested by generating a transgenic
and Cys96 of (cid:12)c are involved in the covalent dimeri- mouse strain that expresses IL-5R(cid:11) ubiquitously by
zation (Stomski et al., 1998). IL-3 was shown to the constitutive promoter of the phosphoglycero-
induce disulfide-linked dimerization between IL-3R(cid:11) kinase 1 (PGK) gene (Takagi et al., 1995). Bone
and (cid:12)c, which is required for receptor activation but marrow cells of the transgenic mice formed colonies
not for high-affinity binding (Stomski et al., 1996). It of various lineages and mixed colonies in response
was also reported that (cid:12)c forms an inactive dimer in to IL-5 in a manner similar to IL-3, indicating that
the absence of cognate ligand and is activated by the limited activity of IL-5 is mainly due to the
binding of a cytokine (Muto et al., 1996). These restricted expression of IL-5R(cid:11) and that IL-5R(cid:11) is
results suggest that the activated receptor complex functionallyequivalenttoIL-3R(cid:11).Theresultsfurther
may be a multimeric complex. suggest that hematopoietic cells have their own
Polymerase chain reaction (PCR)-based random differentiation program which is not affected by the
mutagenesis of the (cid:12)c subunit led to identification (cid:11) subunits. However, it should be noted that the
ofseveralmutationsthatresultinconstitutivedimeri- cytoplasmic domains of the (cid:11) subunits are required
zation of (cid:12)c (Jenkins et al., 1995; Jenkins et al., for signaling.
1998). Mutations in the extracellular domain of (cid:12)c
are clustered in the membrane-proximal domain
MICE DEVOID OF THE IL-3,
(domain 4). Two mutations in the transmembrane
GM-CSF, AND IL-5 RECEPTORS
domain were found and one of them (V449E) is
similar to the constitutive active mutant of the Neu/
ErbB oncogene. Interestingly, mutations at two As there are two IL-3 receptors in the mouse
positions (R461C,H and H544R) in the cytoplasmic (Miyajima et al., 1993), either (cid:12) or (cid:12)c may be
IL3
domain also result in constitutive activity. Whether dispensable for IL-3 function, whereas (cid:12)c is crucial
these constitutive active (cid:12)c form either a dimer or a forIL-5andGM-CSF.Totesttheroleofeach(cid:12) sub-
more complex structure remains unknown. unit, mice devoidofeitheroneofthe (cid:12) subunitswere
generated (Nishinakamura et al., 1995). As expected,
the (cid:12) -deficient mice showed no apparent pheno-
EXPRESSION OF THE IL3
type and no hematological defect was found. In con-
RECEPTOR SUBUNITS
trast, bone marrow cells of the (cid:12)c-deficient mice did
not form any colonies in the presence of either GM-
Expressionof(cid:11)and(cid:12)subunitsoftheIL-3/GM-CSF/ CSForIL-5,whileIL-3-inducedcolonyformationwas
IL-5 receptors is mainly restricted to hematopoietic normal,indicatingthat(cid:12)cisessentialforthefunction
cells (Sato et al., 1993a), while some expression is of GM-CSF and IL-5. A significant reduction of the
1894 Atsushi Miyajima
number of eosinophils in the peripheral blood was the double knockout mice lacking both (cid:12)c and IL-3
noticed in the (cid:12)c-deficient mouse, consistent with the were completely resistant to infection by Listeria
idea that IL-5 is the major cytokine for eosinophil monocytogenes (Nishinakamura et al., 1996). Thus,
development (Takatsu et al., 1994). This is consistent it appears that IL-3, GM-CSF, and IL-5 are largely
with the observation that IL-5R(cid:11) knockout mice dispensable even in emergency situations and the
exhibited only a basal level of eosinophils. In defects can be compensated by other unknown
addition, IL-5R(cid:11) knockout mice showed decreased mechanism.
numbers of B-1 cells concomitant with low serum ConsistentwiththenotionthatIL-3isdispensable,
concentrations of IgM and IgG3 (Yoshida et al., naturally occurring mice with IL-3 hyporesponsive-
1996). ness were found. It was known that several mouse
The(cid:12)c-deficientmiceexhibitedlungabnormalities, strains such as A/J show hyporesponsiveness to IL-3.
including accumulation of proteinous material in the Molecular genetic analysis revealed that the defect is
alveolar spaces and peribronchovascular lymphocytic duetoasmalldeletion(fourbasepairs)inthebranch
infiltration. These observations are probably attribu- point in intron 7 of the IL-3R(cid:11) gene. As branch
table to the deficiency of GM-CSF function as the points are required for proper splicing, the A/J
same phenotype was observed in the GM-CSF-defi- mouse produces mostly aberrant IL-3R(cid:11) mRNA
cient mice (Dranoff et al., 1994). Alveolar macro- (Ichihara et al., 1995). Curiously, the same mutation
phages may play a role in lung homeostasis by was found in 10 out of 27 laboratory mouse strains
clearingsurfactantandotherdebrisfromthealveolar we analyzed. These mouse strains include A/J, C58J,
space and the function of these macrophages may be A/WySnJ, A/HeY, RF/J, AKR/J, SM/J, BUB/BnJ,
impaired in such mice. CE/J, and NZB/BINJ (Hara et al., 1995).
The apparently normal hematopoiesis in the (cid:12)c-
deficient mice may be due to the presence of the
SIGNAL TRANSDUCTION
functional IL-3 receptor consisting of (cid:12) . As IL-3
IL3
knockout mice were generated and were apparently
normal, the IL-3 ligand knockout mouse was crossed IL-3,GM-CSF, and IL-5 induce rapid tyrosine phos-
with the (cid:12)c knockout mouse to generate a mouse phorylation of various cellular proteins including the
linelackingtheentirefunctionofIL-3,GM-CSF,and (cid:12) subunit, phosphatidylinositol 3-kinase, Vav, Shc,
IL-5 (Nishinakamura et al., 1996). Interestingly, the andPTP-1D(Miyajimaetal.,1993;Itohetal.,1996).
mice developed normally and were fertile. Hema- While members of the Src family of tyrosine kinases,
topoiesisinthesemicewassimilartothe(cid:12)cknockout. such as Lyn and Fyn, as well as Btk, a member of
While the eosinophil number was reduced and lung another tyrosine kinase family, were initially shown
disease developed in the double knockout mice, the to be involved in signaling in certain cell types
severity was not changed compared to that of (cid:12)c (Torigoeetal.,1992;Lietal.,1995),therolesofthese
mutant mice. Thus, the entire function of IL-3, GM- kinases in IL-3/GM-CSF signaling still remain
CSF, and IL-5 is dispensable for hematopoiesis in unknown. In contrast, JAK kinases are now believed
normal life. toplayamajorroleincytokinesignaling(Ihle,1995),
Sinceamajorsource ofthesecytokinesisactivated and JAK2 was found to bind to the (cid:12) subunits. The
T cells and basal levels of these cytokines are almost conserved motif among various cytokine receptors
negligible in the normal bone marrow, it is possible knownasBox-1ispresentinthemembrane-proximal
that the major role of these cytokines is to promote regionofthe(cid:12)csubunit(between455and544)andis
hematopoiesis in an emergency situation such as in- sufficientforactivationofJAK2(Quelleet al.,1994),
flammation(Araietal.,1990).Toaddressthequestion followed by activation of signal transducer and acti-
whether these cytokines are essential for emergency vator of transcription 5 (STAT5) (Figure 2). STAT5
hematopoiesis, the mutant mice were infected with activation leads to the induction of various genes
parasitesandbacteria.IL-5R(cid:11)knockoutmiceshowed such as Pim-1, Id-1, CIS, and OSM (Yoshimura
sensitivity to infection with Angiostrongylus canto- et al., 1995, 1996; Mui et al., 1996). This region is
nensis (Sugaya et al., 1997). While IL-3 was shown also responsible for induction of several cytokine-
nottoberequiredforthegenerationofmastcellsand inducible genes, including c-myc. The signals derived
basophils, it was recently shown to contribute to from the membrane-proximal region are important
increasesinthenumbersoftissuemastcells,enhanced for DNA replication and cell cycle progression.
basophil production and immunity in mice infected Themoredistalportion(544–626)of(cid:12)cisrequired
with the nematode Stronglyoides venezuelensis (Lantz for activation of Ras, Raf, MAP kinase and PI-3
et al., 1998). However, the susceptibility to infection kinase as well as induction of c-fos and c-jun (Sato
appearstoberatherrestrictedtoparticularcases,and et al., 1993b; Itoh et al., 1996). Analysis of signaling
Hematopoietic Receptor Family 1895
Figure 2 Signal transduction pathways from the IL-3/IL-5/GM-CSF receptors. JAK2 kinase is
associated with the (cid:12) subunit and is activated by cytokine binding. The activated JAK2 induces
various signals. Ras activated by SOS in turn activates the Raf/MAP kinase pathway and also PI-3
kinase.PI-3kinasecanbeactivateddirectlybythereceptoraswell.TheactivatedSTAT5translocates
tothenucleusandinducesvariousgenes,includingCIS,anegativefeedbackregulatorwhichturnsoff
theSTAT5pathway.STAM1appearstolinkJAK2andinductionofc-myc.Cellproliferationrequires
signals for suppression of cell death and for cell cycle progression; antiapoptotic signals are mainly
delivered by the Ras pathway and signals for cell cycle progression are derived from the membrane-
proximal region of the (cid:12) subunit.
Cytokine
Jak2
Grb
Shc
Sos
SSTTAATT55 STAM
PTPase
Ras
CIS
Raf
PI3K
MAPKK
c-Akt
MAPK
c-Myc
CIS, OSM
c-Fos ? Id, Pim,etc.
etc.
Anti-apoptosis Cell Cycle Progression
Growth
1896 Atsushi Miyajima
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