The long-term goal of our laboratory is to understand how specific protein kinase signaling pathways and phosphoserine/threonine-binding domains regulate cell cycle progression and the response to DNA damage. In response to genotoxic stress, cells activate two canonical protein kinase pathways, the ATR-Chk1 pathway, and the ATM-Chk2 pathway. We recently identified a third DNA damage response pathway mediated by p38MAPK and MAPKAP Kinase-2 (MK2) that is absolutely essential for p53-defective tumor cells to survive after DNA damage. Importantly, this pathway is largely dispensable in cells with intact p53 function, making it an ideal target for specifically impairing the DNA damage response in cancer cells. Furthermore, unlike the ATR-Chk1 and ATM-Chk2 pathways that are dedicated to responding solely to signals from DNA damage per se, the p38 MAPK-MK2 pathway is a much more global stress-response pathway that can also be activated by other types of cellular stress, and plays a critical role in cytokine production during inflammation and tumorigenesis Thus, we believe that the p38MAPK-MK2 pathway plays a particularly novel role during oncogenic and genotoxic stress by integrating DNA damage response pathways within tumor cells with inflammation and cytokine signaling in the adjacent tumor microenvironment. In this proposal we define the role of MK2 in both tumor development and therapeutic response using novel conditional knock-out mouse models, identify the molecular mechanism by which MK2 regulates the G1/S checkpoint, and define its role in post-transcriptional regulation of gene expression through phosphorylation of RNA-binding proteins, which we then explore through a structural and mechanistic approach. Finally, we identify new MK2, Chk1 and Chk2 substrates involved in cell cycle control and DNA damage responses. Data emerging from the proposed experiments should (1) substantially enhance our understanding of the roles of tumor- and stromal derived MK2 in cancer development and progression, (2) expand our knowledge of signaling pathways that control environmental risk for cancer, and (3) identify and validate new molecular targets against which both cancer prevention strategies and anti-cancer therapies can be designed, including MK2 itself and RNA-binding proteins.
Human tumors frequently develop in the setting of inflammation, and contain mutations that affect their response to DNA damage. Defects in how tumor cells respond to DNA damage not only underlie cancer development, but also explain why tumors are killed by chemotherapy and radiation treatment. We believe that the protein kinase MK2 functions as a lynchpin at the crossroads of inflammation and cancer, and that therapeutic targeting of this molecule will both reduce the incidence of tumor formation in response to environmental/inflammatory stimuli, and dramatically enhance the ability of tumor cells to be killed by conventional anti-cancer agents.
|Morton, Stephen W; Lee, Michael J; Deng, Zhou J et al. (2014) A nanoparticle-based combination chemotherapy delivery system for enhanced tumor killing by dynamic rewiring of signaling pathways. Sci Signal 7:ra44|
|Peterson, Laura B; Yaffe, Michael B; Imperiali, Barbara (2014) Selective mitogen activated protein kinase activity sensors through the application of directionally programmable D domain motifs. Biochemistry 53:5771-8|
|Floyd, Scott R; Pacold, Michael E; Huang, Qiuying et al. (2013) The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature 498:246-50|
|Reinhardt, H Christian; Yaffe, Michael B (2013) Phospho-Ser/Thr-binding domains: navigating the cell cycle and DNA damage response. Nat Rev Mol Cell Biol 14:563-80|
|Kang, Seong A; Pacold, Michael E; Cervantes, Christopher L et al. (2013) mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science 341:1236566|
|Qian, Wen-Jian; Park, Jung-Eun; Lim, Dan et al. (2013) Peptide-based inhibitors of Plk1 polo-box domain containing mono-anionic phosphothreonine esters and their pivaloyloxymethyl prodrugs. Chem Biol 20:1255-64|
|Rock, Jeremy M; Lim, Daniel; Stach, Lasse et al. (2013) Activation of the yeast Hippo pathway by phosphorylation-dependent assembly of signaling complexes. Science 340:871-5|
|Weingeist, David M; Ge, Jing; Wood, David K et al. (2013) Single-cell microarray enables high-throughput evaluation of DNA double-strand breaks and DNA repair inhibitors. Cell Cycle 12:907-15|
|Tentner, Andrea R; Lee, Michael J; Ostheimer, Gerry J et al. (2012) Combined experimental and computational analysis of DNA damage signaling reveals context-dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress. Mol Syst Biol 8:568|
|Kholodenko, Boris; Yaffe, Michael B; Kolch, Walter (2012) Computational approaches for analyzing information flow in biological networks. Sci Signal 5:re1|
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