<p>The Abl family of protein tyrosine kinases regulates diverse cellular processes by coordinating cytoskeletal rearrangements. Recent data indicate that pharmacological inhibition of Abl kinases reduces inflammation in preclinical models and in the clinic. While a previous role for Abl kinases in lymphocytes had been described, it remained unclear if Abl kinases regulate innate immune function. To explore this possibility, we generated a myeloid-specific conditional Abl knockout mouse. Using a combination of molecular, genetic, and pharmacological approaches, we demonstrate a role for Abl kinases in regulating the efficiency of macrophage phagocytosis and inflammatory responses. Bone marrow-derived macrophages from mice lacking Abl and Arg kinases exhibit inefficient phagocytosis of sheep erythrocytes and zymosan particles. Treatment with the Abl kinase inhibitors imatinib and GNF-2 or overexpression of kinase-inactive forms of the Abl family kinases also impairs particle internalization in murine macrophages, indicating Abl kinase activity is required for efficient phagocytosis. Further, Abl kinases are present at the phagocytic cup and are activated by Fcgamma receptor engagement. The regulation of phagocytosis by Abl family kinases is mediated in part by the Syk kinase. Loss of Abl and Arg expression or treatment with Abl inhibitors reduced Syk phosphorylation in response to Fcgamma receptor ligation. The link between Abl family kinases and Syk may be direct as purified Arg kinase phosphorylates Syk in vitro. Further, overexpression of membrane-targeted Syk in cells treated with Abl kinase inhibitors partially rescues the impairment in phagocytosis.</p><p>Our studies also revealed a role for Abl kinases in macrophage and cancer cell invasion. Inhibition of Abl kinases suppressed cell invasion in vitro, whereas overexpression of Abl kinases enhanced extracellular matrix degradation. We found that partial loss of Abl kinase expression in myeloid cells reduced macrophage infiltration into tumors in a mouse model of breast cancer. Furthermore, pharmacological inhibition of Abl kinases reduced myeloid cell infiltration and slowed tumor growth in subcutaneous tumor models. We also found that Abl expression and activity are elevated in subsets of human tumor samples. Taken together, our results suggest Abl kinases have an important role in cancer and inflammation, and represent important therapeutic targets for their treatment.</p> / Dissertation
| Identifer | oai:union.ndltd.org:DUKE/oai:dukespace.lib.duke.edu:10161/7167 |
| Date | January 2013 |
| Creators | Greuber, Emileigh |
| Contributors | Pendergast, Ann Marie |
| Source Sets | Duke University |
| Detected Language | English |
| Type | Dissertation |
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