Immune response - CXCR4 signaling via second messenger

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CXCR4 signaling via second messengers

Chemokine (C-X-C motif) receptor-4 (CXCR4) is a G protein-coupled receptor (GPCR). CXCR4 is the only known receptor for Stromal-derived factor-1 (SDF-1), and SDF-1 is the only known ligand for CXCR4 [1].

CXCR4 is expressed in cells of immune and central nervous systems, haematopoietic stem cells. CXCR4 was also found on the surface of primordial germ cells, skeletal muscle satellite progenitor cells, neural stem cells, liver oval/stem cells and retinal pigment epithelium progenitors murine embryonic stem cells. SDF-1 is expressed/secreted by several tissues/organs in the body (bone marrow-, lymph node-, muscle- and lung-derived fibroblasts liver and kidney cells and in several regions of the central nervous system). SDF-1-CXCR4 signaling plays an important and unique role in the regulation of stem/progenitor cell trafficking, inflammation, embryo/organogenesis and tissue/organ regeneration. Association of SDF-1 with CXCR4 activates multiple signaling pathways [2].

SDF-1 stimuli activate receptor and promote interaction between the receptor and the trimeric G-protein alpha (i), beta/gamma. This causes the exchange of GDP for GTP bound to G protein alpha subunits and the dissociation of the beta/gamma heterodimers.

The G-protein beta/gamma heterodimers activate PI3K gamma, recruiting noncatalytic p101 subunit and directly stimulating catalytic p110 gamma subunits. PI3K converts phosphatidylinositol 4,5-biphosphate [PI(4,5)P2] to phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P3], [3]. PI(3,4,5)P3 is a second messenger that directly binds to PtdIns (3,4,5)P3-dependent protein kinase-1 (PDK1) and protein kinase B (AKT). PDK phosphorylates AKT, AKT in turn, activates Inhibitor of nuclear factor kappa-B kinase (IKK), and IKK phosphorylates the I-kappa-B (I-kB) proteins, making them available for destruction via the ubiquitination pathway, thereby allowing activation of the NF-kappa-B (NF-kB) complex.

SDF-1 induces tyrosine phosphorylation of Leukocyte common antigen precursor phosphatase CD45 and its association with CXCR4. CD45-mediated dephosphorylation of Src family tyrosine-protein kinases FYN and LCK activates these kinases. Activated LCK promotes the recruitment and subsequent activation of another tyrosine kinase ZAP70 [4], which in turn regulates phosphorylation of adaptor proteins, Lymphocyte cytosolic protein (SLP-76) and Linker for activation of T cells (LAT). The binding of both LAT and SLP-76 via the ITK SH3 and SH2 domains mediates the optimal activation of PLC gamma1. G-alpha q11 activates phospholipase C beta (PLC-beta). PLC beta hydrolyses PI(4,5)P2 to generate two second messengers inositol 1,4,5-trisphosphate (IP3) and 1,2-diacyl-glycerol (DAG). IP3 generation leads to an increase of the intracellular concentrations of free Ca2+. DAG activates protein kinase C (PKC-theta). PKC-theta in turn, activates IKK and of the NF-kB complex [5].

References:

  1. Murdoch C
    CXCR4: chemokine receptor extraordinaire. Immunological reviews 2000 Oct;177:175-84
  2. Kucia M, Jankowski K, Reca R, Wysoczynski M, Bandura L, Allendorf DJ, Zhang J, Ratajczak J, Ratajczak MZ
    CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. Journal of molecular histology 2004 Mar;35(3):233-45
  3. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
  4. Kremer KN, Humphreys TD, Kumar A, Qian NX, Hedin KE
    Distinct role of ZAP-70 and Src homology 2 domain-containing leukocyte protein of 76 kDa in the prolonged activation of extracellular signal-regulated protein kinase by the stromal cell-derived factor-1 alpha/CXCL12 chemokine. Journal of immunology (Baltimore, Md. : 1950) 2003 Jul 1;171(1):360-7
  5. Helbig G, Christopherson KW 2nd, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, Broxmeyer HE, Nakshatri H
    NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. The Journal of biological chemistry 2003 Jun 13;278(24):21631-8

  1. Murdoch C
    CXCR4: chemokine receptor extraordinaire. Immunological reviews 2000 Oct;177:175-84
  2. Kucia M, Jankowski K, Reca R, Wysoczynski M, Bandura L, Allendorf DJ, Zhang J, Ratajczak J, Ratajczak MZ
    CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. Journal of molecular histology 2004 Mar;35(3):233-45
  3. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
  4. Kremer KN, Humphreys TD, Kumar A, Qian NX, Hedin KE
    Distinct role of ZAP-70 and Src homology 2 domain-containing leukocyte protein of 76 kDa in the prolonged activation of extracellular signal-regulated protein kinase by the stromal cell-derived factor-1 alpha/CXCL12 chemokine. Journal of immunology (Baltimore, Md. : 1950) 2003 Jul 1;171(1):360-7
  5. Helbig G, Christopherson KW 2nd, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, Broxmeyer HE, Nakshatri H
    NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. The Journal of biological chemistry 2003 Jun 13;278(24):21631-8

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