Chemokines are small globular proteins that classically direct immune cell migration, or chemotaxis, to sites of tissue damage and infection. On a cellular level, chemokines mediate their effects via chemokine receptors, cell-membrane proteins belonging to the canonical seven-transmembrane receptor (7TMR) superfamily. Chemokine binding to chemokine receptors initiates signaling cascades ending in cytoskeletal reorganization and chemotaxis towards areas of increasing chemokine concentration. In addition to their immune functions, chemokine networks have been implicated in the growth and metastasis of human cancers. Many tumors increase chemokine and chemokine receptor expression in response to chemotherapy and radiation, limiting the effectiveness of these standard treatment regimens. Of particular importance in mediating tumor growth and metastasis are the chemokine receptors CXCR4 and CXCR7, which share the chemokine ligand CXCL12. Interestingly, chemokine receptors elicit specific cellular outcomes by uniquely recruiting the intracellular proteins G protein and ?-arrestin. Specifically, ?-arrestin recruitment to CXCR4 is essential for cells to undergo chemotaxis, and it may play a critical role in regulating tumor cell metastasis. Further complicating their role in tumorigenesis, chemokine receptors may share multiple chemokine and therapeutic ligands, termed chemokine receptor promiscuity. For instance, CXCR4 and CXCR7 share the therapeutic ligands Plerixafor and TC14012 in addition to sharing CXCL12. The goal of this fellowship is to use Nuclear Magnetic Resonance (NMR) and human pancreatic cancer cells as complementary methods to test the hypothesis that chemokine and therapeutic ligand binding to CXCR4 and CXCR7 leads to activation of distinct signaling cascades and cellular behaviors through unique receptor conformations. The research project will be divided into three specific aims: 1) test the hypothesis that chemokine and therapeutic ligands achieve promiscuity for CXCR4 and CXCR7 through common structural interactions; 2) test the hypothesis that distinct conformations of CXCR4 and CXCR7 allow each receptor to preferentially recruit G protein and ?-arrestin; and 3) test the hypothesis that chemokine and therapeutic ligands mediate chemotaxis in human pancreatic cancer cells by preferentially activating G protein and ?- arrestin pathways. By understanding the fundamental structural characteristics underlying chemokine ligand- receptor interactions in tumor progression, better and more specific therapeutics can be developed for the treatment of a broad range of human cancers.
Chemokines are small, secreted proteins that interact with chemokine receptors on the surface of tumor cells to cause tumor growth and metastasis in many human cancers. Understanding how structural interactions between chemokines and their receptors lead to different tumor behaviors will allow scientists to develop drugs that manipulate tumors on a molecular level, leading to better patient outcomes.
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| Thomas, Monica A; Kleist, Andrew B; Volkman, Brian F (2018) Decoding the chemotactic signal. J Leukoc Biol 104:359-374 |
| Ziarek, Joshua J; Kleist, Andrew B; London, Nir et al. (2017) Structural basis for chemokine recognition by a G protein-coupled receptor and implications for receptor activation. Sci Signal 10: |
| Kleist, Andrew B; Getschman, Anthony E; Ziarek, Joshua J et al. (2016) New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model. Biochem Pharmacol 114:53-68 |
