Receptor

IL-3, like most other 4-helix-bundle cytokines, binds to an oligomeric receptor made up of subunits that are members of a family of proteins termed the 'cytokine or hemopoietin receptor superfamilv'. IL-3 binds with relatively low affinity to a specific ct-chain receptor subunit (IL-3Rct). High-affinity binding and signal transduction requires interaction of the IL-3-IL-3Ra complex with a larger (3-chain receptor sub-unit. This p chain is shared with the GM-CSF and IL-5 receptors (each of which have a GM-CSF- or IL-5-specific a chain) and is thus termed '3 common' or |3C. In the mouse, the situation is more complex in that the complex of IL-3 and IL-3Rcx can also interact with an IL-3-specific (3 chain (A1C-2A or 311.-3)s which has resulted from duplication of the pc gene and itself has low affinity for IL-3.

Binding of IL-3 to the IL-3Ra occurs with relatively low affinity and is followed by interaction with a pc, or, in the mouse, 3ii _j, and the formation of a high-affinity complex. The resultant approximation of the cytoplasmic domains of the a and (3 chains is probably sufficient to activate cytoplasmic tyrosine kinases such as JAK2 kinase, which is known to be activated following binding of IL-3 to its receptor. More complex mechanisms that require the assembly of a larger complex, resulting from recruitment of an additional 3 chain or of other II.-3-IL-3Roi/3 chain complexes, however, have not been completely excluded. Interaction of IL-3 with its receptor results in activation of many of the intracellular signaling paths also stimulated by other growth factors. These include activation of Ras and three branches of the MAP kinase family, the ERK-1,2 Map kinases, the JNK/SAPK kinases, and the p38MAP kinases. These in turn activate other kinases, in the case of Erk-1/2, p90RSK and in the case of p38MAP kinase, MAPKAP-2 kinase. The Map family kinases also directly phosphorylate transcription factors such as c-Jun, ATF-2, CREB, Elk-1 and Sap, upregulating their activity. IL-3 induces upregulation of the expression of genes such as c-myc, c-fos, c-jun, bcl-2 and bclx,. Phosphatidylinositol 3 kinase is also activated. Activation of the transcription factor STAT5 is a relatively specific consequence of IL-3 stimulation, although it also occurs in response to GM-CSF, and IL-5, and IL-2 and prolactin. When activated by tyrosine phosphorylation and dimcr-ization, STAT5 upregulates expression of a series of genes including those encoding oncostatin-M and Cis, as well as contributing to upregulation of expression of c-fos.

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