Chemokine Signaling Pathways

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Overview of Chemokine Signaling Pathways

Chemokines are a large family of small (typically 8-14 kDa), chemoattractant proteins that play a central role in controlling leukocyte migration during development, homeostasis, and inflammation. Following secretion, soluble chemokines or those localized to cell surfaces or the extracellular matrix through their interactions with glycosaminoglycans, establish concentration gradients that direct the migration of cells expressing their cognate receptors. To date, approximately 50 human and/or mouse chemokines have been identified. This group of proteins has been further divided into four subfamilies known as the C chemokines, CC chemokines, CXC chemokines, and CX3C chemokines, based on the number and spacing of conserved cysteine residues located in the amino-terminus. While there are considerable species-specific differences in the members of these subfamilies in mice and humans, 2 C chemokine subfamily members (XCL1 and XCL2), 27 CC chemokine subfamily members (CCL1-CCL28, where mouse Ccl9/10 is the same protein), 17 CXC chemokine subfamily members (CXCL1-CXCL17), and 1 CX3C subfamily member (CX3CL1) have been described in these two species combined. In addition to their subfamily classification, chemokines are classified as either homeostatic or inflammatory based on their expression patterns and functions. Homeostatic chemokines are constitutively produced and function in stem, progenitor, or immune cell trafficking during development and in normal steady-state conditions, while inflammatory chemokines are induced in response to inflammatory stimuli and mediate immune cell trafficking in response to infection or tissue damage.

Chemokines activate their target cells by signaling through seven transmembrane G protein-coupled receptors (GPCRs). To date, 18 conventional chemokine receptors have been identified including 1 C chemokine subfamily receptor (XCR1), 10 CC chemokine subfamily receptors (CCR1-CCR10), 6 CXC chemokine subfamily receptors (CXCR1-CXCR6), and 1 CX3C chemokine subfamily receptor (CX3CR1). Within these subfamilies, many chemokines can bind to more than one receptor and many chemokine receptors can be activated by more than one ligand. This promiscuity, coupled with the fact that different immune cell types typically express more than one chemokine receptor, makes the chemokine system particularly complex in terms of delineating the functional significance of one chemokine versus another in different processes. Additionally, chemokines activate multiple downstream signaling pathways, which can vary somewhat depending on the chemokine, the receptor that it activates, and the target cell type. The graphic shows the pathways that chemokines generally activate and is not tailored to any specific chemokine, receptor, or target cell.

Chemokine signaling is initiated following ligand-receptor binding and activation of the receptor-associated, heterotrimeric Gi-type G protein by GDP/GTP exchange, which leads to dissociation of the G alphai and G beta-gamma subunits. The G beta-gamma subunits activate Class 1B PI 3-Kinase and PLC-beta (PLC). Class 1B PI 3-Kinase, consisting of a p101 regulatory subunit and a p110 gamma catalytic subunit, subsequently phosphorylates and activates multiple substrates including Itk and Akt, which regulate downstream signaling pathways that promote cytoskeleton rearrangements, cell survival, cell growth, and proliferation. Concurrently, PLC hydrolyzes PIP2 to produce inositol-triphosphate (IP3) and diacylglycerol (DAG), which trigger calcium mobilization and Protein kinase C (PKC) activation, respectively. Activation of PKC results in the phosphorylation of IKK, which then phosphorylates I kappa B, promoting its ubiquitin-dependent proteasomal degradation, and allowing NF-kappa B to translocate to the nucleus and induce gene expression. PKC also phosphorylates Focal adhesion kinase (FAK) and Proline-rich tyrosine kinase 2 (PYK2), two non-receptor protein tyrosine kinases. These two kinases phosphorylate substrates such as p130Cas and Paxillin to promote focal adhesion formation and disassembly, cytoskeletal reorganization, and cell migration. At the same time as the G beta-gamma subunits activate these intracellular signaling pathways, the G alphai-GTP-bound subunit of the dissociated G protein inhibits adenylyl cyclase, decreasing intracellular cAMP, and stimulates the kinase activity of Src. Src subsequently phosphorylates multiple downstream substrates including Class IA PI 3-Kinase, Itk, FAK, PYK2, ELMO-1, and Shc. While Itk, FAK, and PYK2 are involved in regulating cytoskeletal reorganization and/or focal adhesion formation as previously described, phosphorylation of ELMO-1 by Src activates signaling pathways that promote cytoskeletal rearrangements required for cell motility. In addition, Src-dependent Shc phosphorylation leads to the recruitment of the GRB2-SOS complex and activation of Ras-MAPK signaling pathways, which mediate cell survival, proliferation, and migration. Along with the intracellular pathways activated by the GTP-bound G alphai and G beta-gamma subunits, chemokine-receptor binding also directly activates the Jak-STAT pathway, which promotes changes in cellular polarization that are required for chemotactic responses.

While chemokines play an essential role in directing cell migration, chemokines and chemokine receptors are also associated with a diverse array of pathological conditions. Due to their abilities to control leukocyte trafficking and inflammatory responses, high chemokine expression levels or unregulated chemokine signaling has the potential to drive excessive or persistent inflammation that is characteristic of chronic inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, multiple sclerosis, diabetes, inflammatory bowel disease, atherosclerosis, asthma, and COPD. Additionally, chemokines are involved in regulating anti-tumor immunity not only by regulating the immune cell composition of the tumor microenvironment, but also by regulating tumor cell proliferation and metastasis. As a result, chemokines and chemokine receptors are being actively investigated as therapeutic targets for the treatment of cancer and inflammatory diseases.

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