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3ok 2

3ok 2

Figure2 Structural organization of the IL-3 receptor« and 0 subunits, both of which are members of the type I cytokine receptor family. The extracellular portion of the IL-3 receptor comprises a conserved motif (stippled boxes), which bears four conserved cysteine residues (CCCC) in the N-terminal side, and the sequence WSXWS in the C-terminal side. A short stretch of conserved amino acid sequence (RFLP) is found in the cytoplasmic domain of the a subunits as well. Box 1 and 2 motifs are part of a serine-rich region in the membrane-proximal domain, which is critical for IL-3-mediated cell proliferation.

also induces transient increases in the tyrosine phosphorylation status of the SH2-containing proteins Vav and p52shr, and facilitates association of the latter with the docking protein GRB-2. These proteins are regulators of the interaction between IL-3R and the Ras pathway (Figure 3).

IL-3 stimulation of the serine/threonine kinases Raf-1 and members of the MAPK cascade serves to link tyrosine kinase-initiated signals to nuclear events involved in mitogenesis. In vitro experiments with glutathione-S-transferase/human II.-3R 3c fusion proteins reveal that the membrane-proximal domain (amino acids 455-517) of the 3c subunit is also capable of directly binding, and being phosphorylated by cytosolic serine/threonine kinases. Interestingly, the IL-3R activates a phosphatidylcholine-specific phospholipase C, in conjunction with membrane translocation and activation of protein kinase (. (PKC). IL-3R-activated PKC phosphorylates Raf-I and the myristoylated alanine-rich C kinase substrate (MARCKS) protein. Phosphorylation of MARCKS is proposed to release the calmodulin bound to it, and lead to activation of calmodulin kinase. Calmodulin appears to be required for IL-3-induced DNA synthesis and primitive hematopoietic progenitor colony formation. Activation of PKC lies downstream of receptor-mediated increases in tyrosine phosphorylation, and seems to play a significant role in both IL-3R-regulated expression of the antiapoptotic gene bcl-2, and the suppression of apoptosis in factor-dependent cells.

Receptor subdomains mediating IL-3-dependent proliferative responses and suppression of apoptosis

Structure-function analyses using cytoplasmic domain deletion mutants of the 3C subunit have revealed two regions which appear to transduce distinct signals, both of which arc required for long-term survival and proliferation (Figure 4). The membrane-proximal region of the human 3c subunit (amino acids 455-562), containing a Pro-X-Pro amino acid motif and an acidic residue-rich region, is required for activation of JAK2 tyrosine kinase and P13K induction of the proto-oncogenes pirn-1, c-myc, and mitogenesis. The amino acid sequence of the membrane-proximal region is highly conserved among 3c, AIC2A and AIC2B (Figure 5). The membrane-distal region (amino acids 626-763) is essential for activation of Ras, Raf-I, MAPK and p70S6K and is related to induction of the c-fos and c-jun genes. A C-terminal-deleted 3<-", which lacks the membrane-distal cytoplasmic sequences required for activation of the Ras-Raf-l-MAPK cascade, induces DNA synthesis, but is incapable of supporting cell survival. Thus, despite a transient mitogenic response, cells expressing this mutant die by apoptosis in the presence of growth factor. Interestingly, the expression of a constitutively activated Ras protein appears to complement defective signaling through this mutant and restores the long-term proliferation response to cytokine stimulation. These data suggest that the IL-3R prevents apoptosis by stimulating a signaling pathway distinct from the induction of DNA synthesis.

See also: Cytokines; Cytokine receptors; Granulocyte-macrophage colony stimulating factor (GM-CSF); Interleukin 3; Interleukin 5 and its receptor.

Figure 3 A generalized schematic illustration of nonreceptor kinases, serine/threonine kinases, downstream effector molecules and target genes involved in IL-3 receptor signaling (proposed pathways indicated by dashed lines). The tyrosine kinases depicted seem to be capable of directly associating with human (Sc. Ligand stimulation leads to increases in (ic tyrosine phosphorylation activation of tyrosine kinases and PI3K, the latter catalyzes formation of the second messenger PI3,4,5-P3 (phosphatidylinositol 3,4,5-triphosphate). PKC£ is known to be activated by PI3,4,5-P3, suggestive of a role for this isotype of PKC in signaling through the IL-3 receptor. Evidence indicates that a 110kDa serine-threonine kinase is also constitutively associated with the (ic subunit the substrates of this enzyme are not yet known. Serine/threonine phosphorylation of STATs is known to enhance their transactivation potential, the pathway/enzyme(s) that mediate this are unknown. IL-3 stimulates the tyrosine phosphorylation and complex formation between adapter proteins regulating activation of the Ras pathway (SHC, SOS-1, GRB-2). However, these events apparently do not promote the mass membrane translocation of the SH2 adapter protein complex. PY, phosphorylated tyrosine: DAG, diacylgly-cerol; Ser/ThrK, serine/threonine kinase.

Figure 3 A generalized schematic illustration of nonreceptor kinases, serine/threonine kinases, downstream effector molecules and target genes involved in IL-3 receptor signaling (proposed pathways indicated by dashed lines). The tyrosine kinases depicted seem to be capable of directly associating with human (Sc. Ligand stimulation leads to increases in (ic tyrosine phosphorylation activation of tyrosine kinases and PI3K, the latter catalyzes formation of the second messenger PI3,4,5-P3 (phosphatidylinositol 3,4,5-triphosphate). PKC£ is known to be activated by PI3,4,5-P3, suggestive of a role for this isotype of PKC in signaling through the IL-3 receptor. Evidence indicates that a 110kDa serine-threonine kinase is also constitutively associated with the (ic subunit the substrates of this enzyme are not yet known. Serine/threonine phosphorylation of STATs is known to enhance their transactivation potential, the pathway/enzyme(s) that mediate this are unknown. IL-3 stimulates the tyrosine phosphorylation and complex formation between adapter proteins regulating activation of the Ras pathway (SHC, SOS-1, GRB-2). However, these events apparently do not promote the mass membrane translocation of the SH2 adapter protein complex. PY, phosphorylated tyrosine: DAG, diacylgly-cerol; Ser/ThrK, serine/threonine kinase.

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