Chemotaxis - CXCR4 signaling pathway

CXCR4 signaling via small GTPases

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

The CXCR4 is expressed in cells of immune and central nervous systems, and 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 progenitor murine embryonic stem cells. SDF-1 is expressed/secreted by several tissues/organs in the body such as 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. Galpha-protein directly stimulates kinase activity of the downregulated Src family kinase tyrosine-protein kinase c-Src, binds to the catalytic domain and changes the conformation of c-Src. In turn, c-Src activates H-Ras-c-Raf-1-MEK1/2-ERK1/2 pathway through phosphorylation of adaptor protein Shc and recruitment of adaptor protein GRB2 and positive regulator of RAS guanine nucleotide exchange protein SOS, leading to the increased transactivation ability of transcription factor Elk1 and the repressed transactivation ability of transcription factor STAT3 which both are phosphorylated by ERK2 [3], [4].

SDF-1alpha activates the JAK/STAT pathway. JAK2 is activated and associated with the CXCR4. This association enables the recruitment, tyrosine phosphorylation and activation of the transcription factor STAT3 [5].

SDF-1 induces tyrosine phosphorylation of CD45 and its association with the CXCR4. CD45-mediated dephosphorylation of Src family kinases Fyn and Lck activates these kinases. Activated Lck promotes the recruitment and subsequent activation of the guanine nucleotide exchange factor VAV1. VAV1 belongs to the family of GTPase exchange factors (GEF). GEFs facilitate the GDP to GTP exchange thereby activating members of the Rho GTPase family such as RhoA, Rac1 and CDC42 that are involved in actin cytoskeleton reorganization. Fyn phosphorylates Pyk2, and Pyk2 associates with VAV1 [6].

SDF-1 stimulates the tyrosine phosphorylation of docking protein 1 (DOK1) by Lck that induces significant association of DOK1 with RAS p21 protein activator (GTPase activating protein) 1 (p120GAP) and v-crk sarcoma virus CT10 oncogene homolog (avian)-like (CrkL). p120GAP reduces H-Ras activity and decreases phosphorylation of ERK1 in response to SDF-1 [7].

Protein-tyrosine phosphatase SHP-2 constitutively associates with CXCR4, and this association is enhanced upon SDF-1 stimulation. SHP-2, which can act as an adaptor molecule, associates with the adaptor molecule c-Cbl. c-Cbl associates with the adaptor proteins CrkL and CRK. Integrin clustering promotes FAK1 autophosphorylation and binding with c-Src. The active FAK1-c-Src complex facilitates SH3-mediated binding of p130CAS and paxillin to FAK1 and its subsequent phosphorylation. CRK is recruited to the nascent focal complex by p130Cas [8].

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. Chang F, Steelman LS, Shelton JG, Lee JT, Navolanic PM, Blalock WL, Franklin R, McCubrey JA
   Regulation of cell cycle progression and apoptosis by the Ras/Raf/MEK/ERK pathway (Review). International journal of oncology 2003 Mar;22(3):469-80
4. Park JI, Strock CJ, Ball DW, Nelkin BD
   Interleukin-1beta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells. Cytokine 2005 Feb 7;29(3):125-34
5. Ahr B, Denizot M, Robert-Hebmann V, Brelot A, Biard-Piechaczyk M
   Identification of the cytoplasmic domains of CXCR4 involved in Jak2 and STAT3 phosphorylation. The Journal of biological chemistry 2005 Feb 25;280(8):6692-700
6. del Pozo MA, Vicente-Manzanares M, Tejedor R, Serrador JM, Sanchez-Madrid F
   Rho GTPases control migration and polarization of adhesion molecules and cytoskeletal ERM components in T lymphocytes. European journal of immunology 1999 Nov;29(11):3609-20
7. Okabe S, Fukuda S, Kim YJ, Niki M, Pelus LM, Ohyashiki K, Pandolfi PP, Broxmeyer HE
   Stromal cell-derived factor-1alpha/CXCL12-induced chemotaxis of T cells involves activation of the RasGAP-associated docking protein p62Dok-1. Blood 2005 Jan 15;105(2):474-80
8. Mitra SK, Hanson DA, Schlaepfer DD
   Focal adhesion kinase: in command and control of cell motility. Nature reviews. Molecular cell biology 2005 Jan;6(1):56-68