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Functional Consequences of Driver Mutations in Novel Cancer-Associated Kinases

John Brognard

Appointment Period: 2007-2008 / Grant Years: [23]

John BrognardUtilizing cancer genome sequencing studies, we have identified loss of function mutations in death-associated protein kinase 3 (DAPK3) in ovarian, lung and colon cancers, implicating this kinase as a tumor suppressor. We have determined that two out of three mutations abolish kinase activity, while the third mutation decreases kinase activity and protein stability. Furthermore, all three DAPK3 cancer mutants act in a dominant negative manner to suppress the function of the wild type enzyme. We observe that overexpression of these mutants suppress the normal function of the kinase, which is to induce apoptosis and inhibit cell cycle progression. Loss of function of this kinase promotes both increased proliferation and cell survival. We have identified myosin light chain kinase 2 as a substrate for DAPK3, and if we target this pathway for activation in cancers harboring loss of function mutations in DAPK3, this results in regression of tumorigenic phenotypes in ovarian, lung and colon cancers. The support from the Growth Regulation & Oncogenesis Training grant has been vital in my initial research efforts to identify DAPK3 as a novel tumor-suppressing kinase, and has provided me a forum to present my research for constructive feedback and ideas.

Brognard J, Newton AC. PHLiPPing the switch on Akt and protein kinase C signaling. Trends Endocrinol Metab. (2008) 19:223-30. PMID: 18511290; PMCID: PMC2963565.

Gao T, Brognard J, Newton AC. The phosphatase PHLPP controls the cellular levels of protein kinase C. J Biol Chem. (2008) 283:6300-11. PMID: 18162466.

Zhang YW, Brognard J, Coughlin C, You Z, Dolled-Filhart M, Aslanian A, Manning G, Abraham RT, Hunter T. The F box protein Fbx6 regulates Chk1 stability and cellular sensitivity to replication stress. Mol Cell. (2009) 35:442-53. PMID: 19716789; PMCID: PMC2736145.

Brognard J, Niederst M, Reyes G, Warfel N, Newton AC. Common polymorphism in the phosphatase PHLPP2 results in reduced regulation of Akt and protein kinase C. J Biol Chem. (2009) 284:15215-23. PMID: 19324870; PMCID: PMC2685702.

Brognard J, Zhang YW, Puto LA, Hunter T. Cancer-associated loss-of-function mutations implicate DAPK3 as a tumor-suppressing kinase. Cancer Res. (2011) 71:3152-61. PMID: 21487036; PMCID: PMC3078168.

Brognard J, Hunter T. Protein kinase signaling networks in cancer. Curr Opin Genet Dev. (2011) 21:4-11. PMID: 21123047; PMCID: PMC3038181.