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Details on Person Upon ligand binding to the alpha subunit, the alpha and Bc s...

Class:IdSummation:879946
_displayNameUpon ligand binding to the alpha subunit, the alpha and Bc s...
_timestamp2010-10-05 12:47:33
created[InstanceEdit:879892] Jupe, S, 2010-06-25
literatureReference[LiteratureReference:450043] Human interleukin-3 (IL-3) induces disulfide-linked IL-3 receptor alpha- and beta-chain heterodimerization, which is required for receptor activation but not high-affinity binding
[LiteratureReference:879924] Mechanism of activation of the GM-CSF, IL-3, and IL-5 family of receptors
[LiteratureReference:913385] The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation
[LiteratureReference:893553] Interleukin-3 stimulates the tyrosine phosphorylation of the 140-kilodalton interleukin-3 receptor
[LiteratureReference:893549] Tyrosine phosphorylation of receptor beta subunits and common substrates in response to interleukin-3 and granulocyte-macrophage colony-stimulating factor
[LiteratureReference:893539] Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation
[LiteratureReference:909750] Evidence for a physical association between the Shc-PTB domain and the beta c chain of the granulocyte-macrophage colony-stimulating factor receptor
[LiteratureReference:879936] JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region
[LiteratureReference:893515] Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit responsible for different signaling
[LiteratureReference:879958] Identification of a viability domain in the granulocyte/macrophage colony-stimulating factor receptor beta-chain involving tyrosine-750
[LiteratureReference:879903] The structural and functional basis of cytokine receptor activation: lessons from the common beta subunit of the granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 receptors
[LiteratureReference:879929] Signaling through the hematopoietic cytokine receptors
modified[InstanceEdit:893547] Jupe, S, 2010-07-01
[InstanceEdit:904809] Jupe, S, 2010-07-02
[InstanceEdit:909735] Jupe, S, 2010-07-07
[InstanceEdit:913398] Jupe, S, 2010-07-14
[InstanceEdit:914195] Jupe, S, 2010-07-23
[InstanceEdit:941871] Jupe, S, 2010-09-06
[InstanceEdit:975839] Jupe, S, 2010-10-05
textUpon ligand binding to the alpha subunit, the alpha and Bc subunits asociate, forming a high affinity receptor. Subsequent signaling may require a disulfide-linked association between the alpha and beta chains (Stomski et al. 1996). While the formation of a 1:1:1 complex of interleukin:alpha subunit:common beta subunit represents a high-affinity binding complex, receptor activation involves the formation of higher order multimeric structures. The stoichiometry of endogenous active receptor complexes is not clear, but studies using dominant-negative, chimeric, and mutant receptors and modeling studies all suggest that a minimum of two Bc subunits are required for receptor activation and signaling (Guthridge et al. 1998, Hansen et al. 2008).

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.
(summation)[BlackBoxEvent:879942] The receptor is activated [Homo sapiens]
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