Melanie Cobb received her undergraduate degree in biochemistry from the University of Chicago and her PhD in biological chemistry from Washington University in St. Louis in the laboratory of Garland Marshall. Following postdoctoral work with Ora Rosen at the Albert Einstein College of Medicine in New York, she joined the Department of Pharmacology at UT Southwestern Medical Center in Dallas where she is currently a Professor and the holder of the Jane and Bill Browning, Jr Chair in Medical Science. Her interests are in cellular regulatory mechanisms.
We study how cells sense and respond to hormones, nutrients, stress and developmental signals in their environment to elucidate regulatory mechanisms with a focus on protein kinase signaling pathways as the targets of these cell stimuli. We are interested in the functions of ERK1/2 MAP kinases in nutrient-sensing pathways, notably in pancreatic beta cells and many cancers, particularly nonsmall cell lung cancer and small cell lung cancer (SCLC). ERK1/2 interfere with survival of SCLC and we are investigating the molecular mechanisms. In studying insulin gene transcription, we determined that ERK1/2 and other regulatory components of the ERK cascade, including the activating MAP2Ks and the phosphatase calcineurin, bind to the insulin gene promoter enabling transcriptional regulation by phosphorylation/dephosphorylation to occur routinely on chromatin. Among other kinase targets, we are investigating mechanisms of action of WNKs, the only protein kinases in the eukaryotic kinase superfamily with a unique position of the catalytic lysine. Altered expression of WNK1 is the cause of Gordon’s syndrome, a rare form of hypertension, and also hereditary and sensory neuropathy type 2. WNK1 forms a complex with the protein kinases OSR1 and SPAK (STK39) and we have identified several ion channels and other proteins regulated by this pathway. Their additional actions on trafficking, the cytoskeleton, and migration in endothelial cells begin to build a picture of the breadth of their functions.
- Graduate School
- Washington University (1976)
- cancer biology
- protein kinase structure/function
- regulation of nutrient responses
- signal transduction mechanisms
- vesicular trafficking
- Radial spoke protein 3 is a mammalian A kinase anchoring protein that binds ERK1/2
- A. Jivan, S. Earnest, Y.C. Juang, and M.H. Cobb. J. Biol Chem. 2009 284 29437-29445
- Multiple chromatin-bound protein kinases assemble factors that regulate insulin gene transcription.
- M.C. Lawrence, C. Shao, K. McGlynn, B. Naziruddin, M.F. Levy, and M.H. Cobb. Proc. Natl, Acad Sci. USA 2009 106 22181-22186
- Mutations in ERK2 binding sites affect nuclear entry.
- Yazicioglu MN, Goad DL, Ranganathan A, Whitehurst AW, Goldsmith EJ, Cobb MH J. Biol. Chem. 2007 Sep 282 39 28759-67
- Biological cross-talk between WNK1 and the transforming growth factor beta-Smad signaling pathway.
- Lee BH, Chen W, Stippec S, Cobb MH J. Biol. Chem. 2007 Jun 282 25 17985-96
- Mxi2 promotes stimulus-independent ERK nuclear translocation.
- Casar B, Sanz-Moreno V, Yazicioglu MN, Rodríguez J, Berciano MT, Lafarga M, Cobb MH, Crespo P EMBO J. 2007 Feb 26 3 635-46
- TAOs mediate activation of p38 in response to DNA damage.
- M. Raman, S. Earnest, K. Zhang, Y. Zhao, and M.H. Cobb. EMBO J. 2007 26 2005-2014
- WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells.
- Anselmo AN, Earnest S, Chen W, Juang YC, Kim SC, Zhao Y, Cobb MH Proc. Natl. Acad. Sci. U.S.A. 2006 Jul 103 29 10883-8
- Starvation activated MAPK through the muscarinic acetylcholine pathway in Caenorhabitis elegans pharynx
- Y-j. You, J. Kim, M. Cobb, and L. Avery. Cell Metabolism 2006 3 237-245
- WNK1 activates SGK1 to regulate the epithelial sodium channel.
- Xu BE, Stippec S, Chu PY, Lazrak A, Li XJ, Lee BH, English JM, Ortega B, Huang CL, Cobb MH Proc. Natl. Acad. Sci. U.S.A. 2005 Jul 102 29 10315-20
- WNK1 phosphorylates synaptotagmin 2 and regulates its ability to associate with membrane vesicles.
- B-H. Lee, X. Min, B-e. Xu, S. Chen, H. Shu, E.J. Goldsmith, and M.H. Cobb. Molecular Cell 2004 15 741-751