Investigating the role of kindlin-3 in protein translation and tumorigenesis via interaction with RACK1
Kindlins are a family of three FERM-containing cytoplasmic proteins that are expressed in various cell types. Kindlins modulate cell-cell and cell-Extracellular Matrix (ECM) interaction by regulating the ligand-binding affinity and avidity of the cell surface adhesion molecules-integrins. Kindlin-3...
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| Format: | Theses and Dissertations |
| Language: | English |
| Published: |
2018
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| Online Access: | http://hdl.handle.net/10356/73451 |
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| Institution: | Nanyang Technological University |
| Language: | English |
| Summary: | Kindlins are a family of three FERM-containing cytoplasmic proteins that are expressed in various cell types. Kindlins modulate cell-cell and cell-Extracellular Matrix (ECM) interaction by regulating the ligand-binding affinity and avidity of the cell surface adhesion molecules-integrins. Kindlin-3 stabilizes β1, β2 and β3 integrins-mediated cell adhesion. It is expressed in hematopoietic cells, platelets and endothelial cells albeit at different levels. Kindlins also interact with other cytoplasmic molecules. Importantly, kindlin-3 has been shown to interact with the scaffold protein Receptor for Activated-C Kinase 1 (RACK1), but the functional consequence of this interaction remains unclear. In this study, we demonstrate that kindlin-3 interacts with the ribosome through RACK1 that serves as a bridging molecule, based on immunoprecipitation assays, in vitro reconstitution experiments and immunofluorescence microscopy. We showed that kindlin-3 regulates c-Myc protein expression in the human Chronic Myelogenous Leukemia (CML) cell line K562. Silencing of kindlin-3 expression reduced K562 cell proliferation in vitro, and tumor growth in vivo. Our data also suggest a role of kindlin-3 in regulating Akt-mTOR-p70S6K signaling that is induced by fibronectin-engaged integrin α5β1; however, the interaction between kindlin-3 and RACK1 and its regulation of c-Myc protein translation is independent of this signaling pathway. In addition, we show that kindlin-3 is a potential target to prevent fibronectin-induced Cell Adhesion-Mediated Drug Resistance (CAM-DR) in CML. Finally, we show that site-specific phosphorylation of kindlin-3 regulates association of kindlin-3 with RACK1. These data provide evidence supporting a role of kindlin-3 in cancer progression and the regulation of protein translation. Protein translation and its regulation are pivotal in cancer progression. Hence, future investigations on the mechanisms of kindlin-3-RACK1 interaction in the context of protein translation regulation will provide useful information for the development of alternative CML therapeutics. |
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