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Regulation Of Cxcr4 Intracellular Trafficking By Ubiquitin, Justine Elizabeth Kennedy

Dissertations

G protein-coupled receptor (GPCR) sorting into the degradative pathway is important for attenuating signaling. Perturbations in this process can manifest in a variety of diseases. Upon agonist activation of the chemokine receptor CXCR4, a GPCR, it is rapidly ubiquitinated, internalized to endosomes and sorted for degradation in lysosomes via the endosomal sorting complex required for transport (ESCRT) pathway. This process culminates in attenuation of CXCR4 signaling. CXCR4 overexpression and increased CXCR4 signaling have been associated with several pathologies including immune deficiency disorders and over 23 cancers. Yet the mechanisms governing the regulation of CXCR4 signaling remain elusive.

CXCR4 is ubiquitinated …

The Endosomal Sorting Complex Required For Transport Pathway Mediates Chemokine Receptor Cxcr4 Akt Signaling By Promoting Lysosomal Degradation Of Mtor Antagonist Deptor, Rita Ramkaran Verma

Dissertations

The chemokine receptor CXCR4 is a member of the G protein-coupled receptor (GPCR) family. The cognate ligand for CXCR4 is the C-X-C chemokine known as CXCL12. The CXCL12/CXCR4 signaling axis is essential for a number of developmental processes including organogenesis, vascularization of the GI tract and hematopoiesis. Dysregulated CXCR4 signaling is also implicated in a variety of pathological conditions such as WHIM (Warts, Hypogammaglobunemia, Infections and myelokathexis) syndrome, cardiovascular disease and cancer. Despite its role in several pathologies, the molecular mechanisms mediating CXCR4 signaling are not completely understood. Upon CXCL12 binding to CXCR4, several signaling pathways are activated including the …

Molecular Mechanisms Regulating Chemokine Receptor Cxcr4 Signaling And Trafficking, Rohit Malik

Dissertations

CXCR4 is a G protein-coupled receptor (GPCR) that binds to the chemokine, stromal cell-derived factor-1 (SDF-1alpha; a.k.a. CXCL12). The SDF-1alpha/CXCR4 signaling axis plays an essential role during embryogenesis in the development of the heart, brain and vasculature and in the adult mediating immune cell trafficking and stem cell homing to the bone marrow. Dysregulation of SDF-1alpha/CXCR4 signaling is linked to several pathological conditions, including cardiovascular disease, immunological disorders as well as cancer growth and metastasis. However, the mechanisms that govern CXCR4 signaling remain poorly understood. In this dissertation project, we attempt to further our understanding of the molecular mechanisms that …

Characterization Of The Coca Chemokine Receptor Four Agonist Activity Of Ubiquitin, Daniel M. Staren

Master's Theses

Ubiquitin has previously been identified as another natural agonist of CXC chemokine receptor 4 (CXCR4). In addition, recent evidence suggests that ubiquitin may activate CXCR4 through a binding site on the receptor, which is distinct from the binding site for the cognate ligand stromal cell-derived factor (SDF)-1α. The cellular consequences of ubiquitin induced CXCR4 activation, however, are still poorly defined and a side-by-side comparison of CXCR4 mediated functions after activation with SDF-1α and ubiquitin is lacking. Such information will be instrumental to better understand the physiological function of CXCR4 and to further define its role as a therapeutic target in …