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Chemotaxis CXCR4 signaling pathway

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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 ), andSDF-1 is the only known ligand for CXCR4 [1].

The CXCR4 is expressed in cells of immune and central nervous systems, andhaematopoietic stem cells. CXCR4 was also found on the surface of primordial germcells, skeletal muscle satellite progenitor cells, neural stem cells, liver oval/stemcells and retinal pigment epithelium progenitor murine embryonic stem cells. SDF-1is expressed/secreted by several tissues/organs in the body such as bone marrow-, lymphnode-, muscle- and lung-derived fibroblasts liver and kidney cells and in several regionsof the central nervous system. SDF-1 - CXCR4 signaling plays an importantand unique role in the regulation of stem/progenitor cell trafficking, inflammation,embryo/organogenesis and tissue/organ regeneration. Association of SDF-1 withCXCR4 activates multiple signaling pathways [2].

SDF-1 stimuli activate receptor and promote interaction between the receptorand the trimeric G-protein alpha (i), beta/gamma. This causes the exchangeof GDP for GTP bound to G protein alpha subunits and the dissociation ofthe beta/gamma heterodimers. G alpha -protein directly stimulateskinase activity of the downregulated Src family kinase tyrosine-protein kinasec-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 Shcand recruitment of adaptor protein GRB2 and positive regulator of RAS guaninenucleotide exchange protein SOS, leading to the increased transactivation abilityof transcription factor Elk1 and the repressed transactivation ability oftranscription factor STAT3 which both are phosphorylated by ERK2 [3], [4].

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

SDF-1 induces tyrosine phosphorylation of CD45 and its association withthe CXCR4. CD45 -mediated dephosphorylation of Src family kinasesFyn and Lck activates these kinases. Activated Lck promotes therecruitment and subsequent activation of the guanine nucleotide exchange factorVAV1. VAV1 belongs to the family of GTPase exchange factors (GEF). GEFsfacilitate the GDP to GTP exchange thereby activating members of the Rho GTPase familysuch as RhoA, Rac1 and CDC42 that are involved in actincytoskeleton reorganization. Fyn phosphorylates Pyk2, and Pyk2associates with VAV1 [6].

SDF-1 stimulates the tyrosine phosphorylation of docking protein 1 (DOK1 ) by Lck that induces significant association of DOK1 with RASp21 protein activator (GTPase activating protein) 1 ( p120GAP ) and v-crk sarcomavirus CT10 oncogene homolog (avian)-like ( CrkL ). p120GAP reducesH-Ras activity and decreases phosphorylation of ERK1 in response toSDF-1 [7].

Protein-tyrosine phosphatase SHP-2 constitutively associates with CXCR4, and this association is enhanced upon SDF-1 stimulation. SHP-2, whichcan act as an adaptor molecule, associates with the adaptor molecule c- Cbl. c-Cbl associates with the adaptor proteins CrkL and CRK. Integrinclustering promotes FAK1 autophosphorylation and binding with c-Src. Theactive FAK1 - c-Src complex facilitates SH3-mediated binding ofp130CAS and paxillin to FAK1 and its subsequent phosphorylation.CRK is recruited to the nascent focal complex by p130Cas [8].