Interleukin-3, Interleukin-5 and GM-CSF signaling (Homo sapiens)
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The Interleukin-3 (IL-3), IL-5 and Granulocyte-macrophage colony stimulating factor (GM-CSF) receptors form a family of heterodimeric receptors that have specific alpha chains but share a common beta subunit, often referred to as the common beta (Bc). Both subunits contain extracellular conserved motifs typical of the cytokine receptor superfamily. The cytoplasmic domains have limited similarity with other cytokine receptors and lack detectable catalytic domains such as tyrosine kinase domains.
IL-3 is a 20-26 kDa product of CD4+ T cells that acts on the most immature marrow progenitors. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3 has been used to support the proliferation of murine cell lines with properties of multi-potential progenitors, immature myeloid as well as T and pre-B lymphoid cells (Miyajima et al. 1992). IL-5 is a hematopoietic growth factor responsible for the maturation and differentiation of eosinophils. It was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells. It also promotes the generation of cytotoxic T-cells from thymocytes. IL-5 induces the expression of IL-2 receptors (Kouro & Takatsu 2009). GM-CSF is produced by cells (T-lymphocytes, tissue macrophages, endothelial cells, mast cells) found at sites of inflammatory responses. It stimulates the growth and development of progenitors of granulocytes and macrophages, and the production and maturation of dendritic cells. It stimulates myeloblast and monoblast differentiation, synergises with Epo in the proliferation of erythroid and megakaryocytic progenitor cells, acts as an autocrine mediator of growth for some types of acute myeloid leukemia, is a strong chemoattractant for neutrophils and eosinophils. It enhances the activity of neutrophils and macrophages. Under steady-state conditions GM-CSF is not essential for the production of myeloid cells, but it is required for the proper development of alveolar macrophages, otherwise, pulmonary alvelolar proteinosis (PAP) develops. A growing body of evidence suggests that GM-CSF plays a key role in emergency hematopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult (Hercus et al. 2009).
All three receptors have alpha chains that bind their specific ligands with low affinity (de Groot et al. 1998). Bc then associates with the alpha chain forming a high affinity receptor (Geijsen et al. 2001), though the in vivo receptor is likely be a higher order multimer as recently demonstrated for the GM-CSF receptor (Hansen et al. 2008).
The receptor chains lack intrinsic kinase activity, instead they interact with and activate signaling kinases, notably Janus Kinase 2 (JAK2). These phosphorylate the common beta subunit, allowing recruitment of signaling molecules such as Shc, the phosphatidylinositol 3-kinases (PI3Ks), and the Signal Transducers and Activators of Transcription (STATs). The cytoplasmic domain of Bc has two distinct functional domains: the membrane proximal region mediates the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. This region binds multiple signal-transducing proteins including JAK2 (Quelle et al. 1994), STATs, c-Src and PI3 kinase (Rao and Mufson, 1995). The membrane distal domain is required for cytokine-induced growth inhibition and is necessary for the viability of hematopoietic cells (Inhorn et al. 1995). This region interacts with signal-transducing proteins such as Shc (Inhorn et al. 1995) and SHP and mediates the transcriptional activation of c-fos, c-jun, c-Raf and p70S6K (Reddy et al. 2000).
Figure reproduced by permission from Macmillan Publishers Ltd: Leukemia, WL Blalock et al. 13:1109-1166, copyright 1999. Note that residue numbering in this diagram refers to the mature Common beta chain with signal peptide removed. View original pathway at Reactome.
IL-3 is a 20-26 kDa product of CD4+ T cells that acts on the most immature marrow progenitors. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3 has been used to support the proliferation of murine cell lines with properties of multi-potential progenitors, immature myeloid as well as T and pre-B lymphoid cells (Miyajima et al. 1992). IL-5 is a hematopoietic growth factor responsible for the maturation and differentiation of eosinophils. It was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells. It also promotes the generation of cytotoxic T-cells from thymocytes. IL-5 induces the expression of IL-2 receptors (Kouro & Takatsu 2009). GM-CSF is produced by cells (T-lymphocytes, tissue macrophages, endothelial cells, mast cells) found at sites of inflammatory responses. It stimulates the growth and development of progenitors of granulocytes and macrophages, and the production and maturation of dendritic cells. It stimulates myeloblast and monoblast differentiation, synergises with Epo in the proliferation of erythroid and megakaryocytic progenitor cells, acts as an autocrine mediator of growth for some types of acute myeloid leukemia, is a strong chemoattractant for neutrophils and eosinophils. It enhances the activity of neutrophils and macrophages. Under steady-state conditions GM-CSF is not essential for the production of myeloid cells, but it is required for the proper development of alveolar macrophages, otherwise, pulmonary alvelolar proteinosis (PAP) develops. A growing body of evidence suggests that GM-CSF plays a key role in emergency hematopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult (Hercus et al. 2009).
All three receptors have alpha chains that bind their specific ligands with low affinity (de Groot et al. 1998). Bc then associates with the alpha chain forming a high affinity receptor (Geijsen et al. 2001), though the in vivo receptor is likely be a higher order multimer as recently demonstrated for the GM-CSF receptor (Hansen et al. 2008).
The receptor chains lack intrinsic kinase activity, instead they interact with and activate signaling kinases, notably Janus Kinase 2 (JAK2). These phosphorylate the common beta subunit, allowing recruitment of signaling molecules such as Shc, the phosphatidylinositol 3-kinases (PI3Ks), and the Signal Transducers and Activators of Transcription (STATs). The cytoplasmic domain of Bc has two distinct functional domains: the membrane proximal region mediates the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. This region binds multiple signal-transducing proteins including JAK2 (Quelle et al. 1994), STATs, c-Src and PI3 kinase (Rao and Mufson, 1995). The membrane distal domain is required for cytokine-induced growth inhibition and is necessary for the viability of hematopoietic cells (Inhorn et al. 1995). This region interacts with signal-transducing proteins such as Shc (Inhorn et al. 1995) and SHP and mediates the transcriptional activation of c-fos, c-jun, c-Raf and p70S6K (Reddy et al. 2000).
Figure reproduced by permission from Macmillan Publishers Ltd: Leukemia, WL Blalock et al. 13:1109-1166, copyright 1999. Note that residue numbering in this diagram refers to the mature Common beta chain with signal peptide removed. View original pathway at Reactome.
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linker
protein:p(Y700,731,774)-CBLreceptor alpha subunit:Common beta
chain:JAK2receptor alpha
subunitaffinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,
p-(Y593,628)-Bc:p(427,349,350)-SHC1affinity binding complex dimers of cytokine receptors using Bc, inactive
JAK2,p(Y593)-Bc:SHP1, SHP2affinity binding complex dimers of cytokine receptors using Bc, inactive
JAK2,p(Y593,628)-Bc:SHP1, SHP2binding complex dimers of cytokine receptors using Bc, activated
JAK2:p-STAT5binding complex dimers of cytokine receptors using Bc,
activated JAK2binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3 zeta:p85-containing
Class 1A PI3Ksbinding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3
zetabinding complex dimers of cytokine receptors using Bc, inactive JAK2,
p(S589)-Bcbinding complex dimers of cytokine receptors using Bc, inactive JAK2,
p(Y593,628)-Bc:SHC1binding complex dimers of cytokine receptors using Bc, inactive JAK2,
p(Y593,628)-Bcbinding complex dimers of cytokine receptors using Bc,
inactive JAK2binding complex dimers of cytokine receptors using Bc. activated
JAK2:STAT5binding complexes of interleukin receptors using the
Common beta chainreceptor complexes with activated
Shc:GRB2:p-GAB2:p85-containing Class 1 PI3Kscompexes with activated
Shc:GRB2:GAB2complexes with activated
SHC1:GRB2:SOS1complexes with activated
SHC1:SHIP1,2complexes with activated
SHC1:SHIP1complexes with activated
SHC1:SHIP:GRB2complexes with activated
Shc:GRB2:p-GAB2complexes with
activated SHC1The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
that phosphorylate the Common beta
chainAnnotated Interactions
linker
protein:p(Y700,731,774)-CBLreceptor alpha subunit:Common beta
chain:JAK2receptor alpha
subunitreceptor alpha
subunitaffinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,
p-(Y593,628)-Bc:p(427,349,350)-SHC1affinity binding complex dimers of cytokine receptors using Bc, inactive
JAK2,p(Y593)-Bc:SHP1, SHP2affinity binding complex dimers of cytokine receptors using Bc, inactive
JAK2,p(Y593,628)-Bc:SHP1, SHP2affinity binding complex dimers of cytokine receptors using Bc, inactive
JAK2,p(Y593,628)-Bc:SHP1, SHP2affinity binding complex dimers of cytokine receptors using Bc, inactive
JAK2,p(Y593,628)-Bc:SHP1, SHP2binding complex dimers of cytokine receptors using Bc, activated
JAK2:p-STAT5binding complex dimers of cytokine receptors using Bc, activated
JAK2:p-STAT5binding complex dimers of cytokine receptors using Bc,
activated JAK2binding complex dimers of cytokine receptors using Bc,
activated JAK2binding complex dimers of cytokine receptors using Bc,
activated JAK2binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3 zeta:p85-containing
Class 1A PI3Ksbinding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3
zetabinding complex dimers of cytokine receptors using Bc, inactive JAK2, p(S589)-Bc:14-3-3
zetabinding complex dimers of cytokine receptors using Bc, inactive JAK2,
p(S589)-Bcbinding complex dimers of cytokine receptors using Bc, inactive JAK2,
p(S589)-Bcbinding complex dimers of cytokine receptors using Bc, inactive JAK2,
p(Y593,628)-Bc:SHC1binding complex dimers of cytokine receptors using Bc, inactive JAK2,
p(Y593,628)-Bc:SHC1binding complex dimers of cytokine receptors using Bc, inactive JAK2,
p(Y593,628)-Bcbinding complex dimers of cytokine receptors using Bc, inactive JAK2,
p(Y593,628)-Bcbinding complex dimers of cytokine receptors using Bc, inactive JAK2,
p(Y593,628)-Bcbinding complex dimers of cytokine receptors using Bc,
inactive JAK2binding complex dimers of cytokine receptors using Bc,
inactive JAK2binding complex dimers of cytokine receptors using Bc,
inactive JAK2binding complex dimers of cytokine receptors using Bc,
inactive JAK2binding complex dimers of cytokine receptors using Bc,
inactive JAK2binding complex dimers of cytokine receptors using Bc. activated
JAK2:STAT5binding complex dimers of cytokine receptors using Bc. activated
JAK2:STAT5binding complex dimers of cytokine receptors using Bc. activated
JAK2:STAT5binding complexes of interleukin receptors using the
Common beta chainreceptor complexes with activated
Shc:GRB2:p-GAB2:p85-containing Class 1 PI3Kscompexes with activated
Shc:GRB2:GAB2compexes with activated
Shc:GRB2:GAB2complexes with activated
SHC1:GRB2:SOS1complexes with activated
SHC1:SHIP1,2complexes with activated
SHC1:SHIP1complexes with activated
SHC1:SHIP:GRB2complexes with activated
Shc:GRB2:p-GAB2complexes with activated
Shc:GRB2:p-GAB2complexes with
activated SHC1complexes with
activated SHC1complexes with
activated SHC1Constitutive activation of JAK2 resulting from the V617F mutation is present in over 95% of Polycythemia Vera patients (Dusa et al. 2010). F595 is indispensible for constitutive activation by V617F, but not for JAK2 activation, suggesting that this is not part of the cytokine-induced mechansim of JAK2 activation.
Tyrosine phosphorylation of Cbl in response to IL-3 releases the SH3 domain of Grb2 which then is free to bind other molecules (Park et al. 1998).
Cbl further associates with the p85 subunit of PI3K (Hartley et al. 1995, Anderson et al. 1997, Hunter et al. 1997), this is also described as constitutive and is mediated by the SH3 domain of p85 (Hunter et al. 1997).Cbl also associates with Fyn (Anderson et al. 1997) and the related kinases Hck and Lyn (Hunter et al. 1999). Binding studies indicate that this binding is independent of the phosphorylation state of Cbl; The association of Fyn with Cbl has been described as constitutive (Hunter et al. 1999).
Residue numbering used here refers to Uniprot P29353 where the p66 isoform has been selected as the canonical form. Literature references given here refer to the p52 isoform which lacks the first 110 residues, so Y427 is referred to as Y317 in Salcini et al. 1994, Y349 and Y350 as Y239 and Y240 in Gotoh et al. 1996.
STAT5 proteins are considered the main targets of IL-3, IL-5 and GM-CSF signaling (Mui et al. 1995a, Mui et al. 1995b, Ihle, 2001), but other members of this family including STAT3 and STAT1 (Chin et al. 1996) can be involved, the STAT family member activated appears to depend on the cell line used in the study, rather than the cytokine (Reddy et al. 2000). IL-5 and GM-CSF increase STAT3 and 5 signaling (Caldenhoven et al. 1995, Stout et al. 2004).
Unphosphorylated STATs are cytoplasmic; tyrosine phosphorylation facilitates dimerization and translocation to the nucleus where they act as transcription factors. STATs were originally described as ligand-induced transcription factors in interferon-treated cells, subsequently they were shown to be critical in many signal transduction pathways associated with cytokines and neurokines including several interleukins, the interferons, erythropoietin, prolactin, growth hormone, oncostatin M (OSM), and ciliary neurotrophic factor (Darnell 1997, Reddy et al. 2000). JAK-STAT signaling is widely accepted as a primary signaling route for receptors that share the common beta subunit (Bc).
The role of the receptor itself in STAT5 binding is somewhat controversial because while STAT proteins can be recruited to tyrosine phosphorylated receptors via their SH2 domains (Greenlund et al. 1995, Li et al. 1997) binding of STAT5 to Bc has not been formally demonstrated (Guthridge et al. 1998), though tyrosine-phosphorylated peptides of Bc have been demonstrated to associate with STAT5, and anti-Bc or phosphotyrosine antibodies inhibited GM-CSF induced STAT5 DNA binding activity (Sakurai et al. 2000). Binding of JAK2 to STAT5 can occur in vitro when no receptor is present (Flores-Morales et al. 1998). STAT5 activation was seen when all six conserved cytoplasmic tyrosines in Bc were mutated to P (Okuda et al. 1997), but a C-terminal deletion mutant of Bc while able to activate JAK2 was unable to activate STAT5 (Smith et al. 1997). These observations suggest that JAK2 activation is a critical step in STAT signaling from Bc-containing receptors, but other factors may be required. It is not clear whether Bc is directly involved or not in STAT5 activation, but the specificity for particular STAT members is believed to be determined by STAT docking sites present on the receptor molecules, not JAK kinase preference (Reddy et al. 2000).
The cytoplasmic region of Bc contains several tyrosines that become phosphorylated on cytokine binding (Sorensen et al. 1989, Duronio et al. 1992, Sakamaki et al. 1992, Pratt et al. 1996). One such site is Y766, numbered according to the Uniprot canonical sequence. Note that in many publications this position is numbered as 750, referring to the mature sequence with signal peptide removed. These phosphorylations are mediated by receptor-associated kinases with JAK2 as the most likely candidate (Quelle et al. 1994, Guthridge et al. 1998). Specific phosphorylations appear to mediate association with different signaling components (Sato et al. 1993), e.g. substitution of F for Y766 prevents Shc phosphorylation (Inhorn et al. 1995) but not JAK2 phosphorylation. Modeling and structural data suggest that the active receptor is at least a dimer of ligand:alpha subunit:common beta subunit complexes (Bagley et al. 1997, Guthridge et al. 1998, Hansen et al. 2008). This fits a model of receptor activation whereby dimerization leads to Jak2 activation by transphosphorylation of the activation sites (Ihle et al. 1995, Guthridge et al. 1998, Hansen et al. 2008), leading to Bc activation by phosphorylation. The active receptors are represented here as dimers of ligand:alpha subunit:common beta subunit complexes.
Tyrosines 700, 731 and 774 are the major sites of Cbl phosphorylation by non-receptor protein tyrosine kinases, with none showing any particular specificity for sites (Tsygankov et al. 2001). Fyn was observed to be constitutively associated with Cbl in lysates of several different cell types including the interleukin-3-dependent murine myeloid cell line 32Dcl3, and the prolactin-dependent rat thymoma cell line Nb2. Cbl phosphorylation at Y731 is postulated to provide an additional interaction between Cbl and the SH2 domain of p85-PI3K (Hunter et al. 1999). Cbl-p85 association increases in activated cells (Panchamoorthy et al. 1996). Expression of a Cbl Y731F mutant which abolishes binding of Cbl to p85 markedly increased levels of p85-PI3K (Dufour et al. 2008). Cbl-p85 binding negatively regulates PI3K activity (Fang et al. 2001); Cbl phosphorylation increased PI3K ubiquitination and proteasome degradation (Dufour et al. 2008). Cbl association with members of the Crk family is mediated by phosphorylation of Y700 and Y774 (Andoniou et al. 1996), binding with Vav is mediated by Y770 (Marengere et al 1997).
that phosphorylate the Common beta
chain