CXCR4 Signaling


Pathway Description

Chemokine (C-X-C motif) Receptor-4 (CXCR4/CD184) is a GPCR with selectivity for a single CXC-motif chemokine, called SDF1. The chemokine receptor CXCR4 is broadly expressed in cells of both the immune and the central nervous systems and can mediate migration of resting leukocytes and haematopoietic progenitors in response to its ligand, SDF1. SDF1 exists in 2 structural variants (SDF1a and SDF1b) that differ by 4 additional amino acids in the carboxyl-terminus of the b-form but show identical receptor binding and activity profiles. It is involved in B lympho- and myelopoiesis, cardiogenesis, blood vessel formation and cerebellar development. SDF1 binding to CXCR4 has shown to elevate intracellular Ca2+, activate MAPK, JNK and PI3K signalling pathways leading to cell growth, migration and polarization. CXCR4 stimulation by SDF1 also results in increased phosphorylation of Focal Adhesion components, including the related adhesion focal tyrosine kinase (RAFTK/PYK2), Crk and Paxillin. Crk, composed of SH2 and SH3 domains, has a putative role in signaling. JNK is moderately activated by v-Crk. The activation of JNK by v-Crk involve the guanine nucleotide exchange proteins SOS or C3G, both of which bind to the Crk SH3 domain, because JNK has recently been reported to be regulated by small G proteins, Rac and Cdc42.CXCR4 is also a major receptor for strains of HIV1 that arise during progression to immunodeficiency and AIDS dementia. CXCR4 binds directly to the GP120 glycoprotein of HIV1 and, together with HIV1 binding to CD4, permits viral infection of T lymphocytes. HIV1 infects target cells via a receptor complex formed by CD4 and a chemokine receptor, primarily CCR5 or CXCR4.

CXCR4 induces downstream signaling by several different pathways. As a GPCR, CXCR4 binding of SDF1 activates G-protein mediated signaling, including downstream pathways such as Ras, and PI3K. The three subunits are: G-α, G-β and G-γ. The G-α subunit has many different functions, depending on its isoform. GQ family controls the activity of phosphatidylinositol-specific phospholipases, such as PLC-β, which hydrolyzes PIP2 to generate two-second messengers, IP3 and DAG.IP3 and DAG in turn lead to an increase in the intracellular concentrations of free Ca2+ and the activation of a number of protein kinases, including PKC. G-αQ is reported to activate the transcription factor NF-κB through PYK2. Both G-αI - and G-αQ-coupled receptors can potently stimulate MAPK activation. Furthermore; stimulation of MAPK activity by co expressed β-γ dimers involved the activation of Ras. The small G-protein Ras becomes activated when its GEF is recruited to the membrane via RTKs,FAK, etc. Once Ras binds GTP, it can then recruit the serine/threonine kinase Raf to the membrane. When Raf translocate to the membrane, it becomes activated and then phosphorylates the dual specificity kinase MEK. This leads to the activation of MEK, which then phosphorylates a critical tyrosine and threonine on ERKs. ERK then phosphorylates and activate other cellular proteins (like p90RSK) as well as translocate into the nucleus and phosphorylate/activate transcription factors (like Elk1) and leads to changes in gene expression and cell cycle progression. Further, β-γ also interacts with ion channels and recruits PI3K-γ to the membrane. PI3K activated by SDF1 and One endpoint of CXCR4 signaling is the activation of transcription factors such as Activating Protein1 and chemokine regulated genes. JAK/STAT (Janus Kinase/ Signal Transducer and Activator of Transcription) signaling pathways also appear to play a role in SDF1/CXCR4 signaling. Recently it has been demonstrated that on T lymphocytes, CXCR4 utilizes both G proteins and components of the TCR to regulate activity of the ERK MAP kinases.