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
- Regulation of insulin gene transcription by ERK1 and ERK2 in pancreatic beta cells.
- Khoo S, Griffen SC, Xia Y, Baer RJ, German MS, Cobb MH J. Biol. Chem. 2003 Aug 278 35 32969-77
- Activation mechanism of the MAP kinase ERK2 by dual phosphorylation.
- B.J. Canagarajah, A. Khokhlatchev, M.H. Cobb, and E.J. Goldsmith. Cell 1997 90 859-869
- ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF.
- T.G. Boulton, S.H. Nye, D.J. Robbins, N.Y. Ip, E. Radziejewska, S.D. Morgenbessor, R.A. DePinho, N. Panayotatos, M.H. Cobb and G.D. Yancopoulos. Cell 1991 65 663-675