Chemokine hfcUzHlUr Signaling

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The intracellular signals involved in chemo-taxis are not yet fully understood, and much of the information available today has been deduced from signaling information for other GPCRs. However, significant new data regarding the chemotactic process have accumulated in recent years. Like other seven-trans-membrane receptors, chemokine receptors couple to G-proteins. Many chemokine-in-duced signaling events are inhibited by Borde-tella pertussis toxin (PTX), suggesting that chemokine receptors are linked to G-proteins of the Gai class (18, 19). In cotransfection experiments it has been shown that CXCRl and

CXCR2 couple to Gai2, Gai3, Gal4, and G<*16 (20). Physical association between Gai and several chemokine receptors has been documented (21, 22). In some studies, PTX did not completely block the calcium response, suggesting the chemokine receptors may couple to other G-proteins such as Gq or Gal6. In addition, it has been suggested that the specificity of the coupling may be cell type specific (23, 24).

Chemokine receptor activation leads to the generation of a complex cascade of cellular events, including the generation of inositol triphosphates, the release of intracellular calcium, and the activation of protein kinase C. The release of the Gai/3y subunits from Gai has been described as an essential step in this process (25). However, the release from Gas or Gaq does not result in induction of chemo-taxis, suggesting that the jSy subunits are necessary but not sufficient to induce cell migration and that Gai itself plays some role in the process (26).

Activation of the chemokine receptor leads to rapid activation of phosphoinositide-spe-cific phospholipases, which leads to inositol-

formation and a transient rise in intracellular calcium (18). Phospho-lipase C (PLC) isoforms that are involved in chemokine receptor activation become activated by direct interaction with the /3-y sub-units. In addition to its interaction with PLCs, the J3y subunits also interact with the type I, phosphoinositol 3 kinase y (PI3Ky), and activation of this enzyme results in the formation of PtdIns(3,4,5)P3 (17). Mice that do not express PI3Ky have severely impaired chemo-kine-stimulated signal transduction, and PKB is not activated, suggesting an important role for this pathway in the chemotactic process Although leukocytes isolated from these mice showed a decrease in cell chemo-taxis, the response is not completely lost, and under conditions of complete PI3Ky inhibition, neutrophils can still chemotax in response to chemokines (30).

Receptor dimerization upon ligand binding has been described mostly for the growth factor receptor; however, recent reports have also suggested heterodimerization for seven-trans-membrane receptors, including chemokine receptors (31-33). It has been proposed that che-

Figure 4.3. Schematic diagram showing the props ed chemokine receptor signaling pathways. This diagram does not represent the complete pathway. Ligand binding induces the exchange of GDP for GTP on the G protein and this causes dissociation of the subunits. Gai decreases the levels of cAMP and GjBy causes the activation of PLC and PI3Ky. PLC, phospholipase C; DAG, diacylglycerol; IP3, inositol triphosphate; PKC, protein kinase C; MAPK, mito-gen-activated protein kinase; PI3K% phosphoinosi-tol 3 kinase y; PKB, protein kinase B.

Figure 4.3. Schematic diagram showing the props ed chemokine receptor signaling pathways. This diagram does not represent the complete pathway. Ligand binding induces the exchange of GDP for GTP on the G protein and this causes dissociation of the subunits. Gai decreases the levels of cAMP and GjBy causes the activation of PLC and PI3Ky. PLC, phospholipase C; DAG, diacylglycerol; IP3, inositol triphosphate; PKC, protein kinase C; MAPK, mito-gen-activated protein kinase; PI3K% phosphoinosi-tol 3 kinase y; PKB, protein kinase B.

okine receptor dimerization results in the activation of the Janus kinase-signal transducers and activator of transcription (JAKSTAT) signaling pathway (34). Figure 4.3 ows a schematic of the pathways involved in receptor signaling.

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