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
- The domain-swapping switch point in Ste20 protein kinase SPAK.
- Taylor CA, Juang YC, Earnest S, Sengupta S, Goldsmith EJ, Cobb MH Biochemistry 2015 Jul
- Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK.
- Dbouk HA, Weil LM, Perera GK, Dellinger MT, Pearson G, Brekken RA, Cobb MH Proc. Natl. Acad. Sci. U.S.A. 2014 Nov 111 45 15999-6004
- Menin determines K-RAS proliferative outputs in endocrine cells.
- Chamberlain CE, Scheel DW, McGlynn K, Kim H, Miyatsuka T, Wang J, Nguyen V, Zhao S, Mavropoulos A, Abraham AG, O'Neill E, Ku GM, Cobb MH, Martin GR, German MS J. Clin. Invest. 2014 Aug
- Muscarinic Control of MIN6 Pancreatic ß Cells Is Enhanced by Impaired Amino Acid Signaling.
- Guerra ML, Wauson EM, McGlynn K, Cobb MH J. Biol. Chem. 2014 Apr
- Chloride Sensing by WNK1 Involves Inhibition of Autophosphorylation.
- Piala AT, Moon TM, Akella R, He H, Cobb MH, Goldsmith EJ Sci Signal 2014 7 324 ra41
- Protein kinase WNK3 regulates the neuronal splicing factor Fox-1.
- Lee AY, Chen W, Stippec S, Self J, Yang F, Ding X, Chen S, Juang YC, Cobb MH Proc. Natl. Acad. Sci. U.S.A. 2012 Oct 109 42 16841-6
- The G Protein-Coupled Taste Receptor T1R1/T1R3 Regulates mTORC1 and Autophagy.
- Wauson EM, Zaganjor E, Lee AY, Guerra ML, Ghosh AB, Bookout AL, Chambers CP, Jivan A, McGlynn K, Hutchison MR, Deberardinis RJ, Cobb MH Mol. Cell 2012 Sep 47 6 851-62
- WNK 1 is required for mitosis and abscission.
- S-W. Tu, K. Luby-Phelps and M.H. Cobb. Proc. Natl, Acad. Sci. USA 2011 108 1385-1390
- Calcineurin increases glucose activation of ERK1/2 by reversing negative feedback.
- L. Duan and M.H. Cobb. Proc. Natl. Acad. Sci. USA 2010 107 22314-22319
- The Epithelial Sodium Channel (aENaC) Is a Downstream Therapeutic Target of ASCL1 in Pulmonary Neuroendocrine Tumors.
- He M, Liu S, Gallolu Kankanamalage S, Borromeo MD, Girard L, Gazdar AF, Minna JD, Johnson JE, Cobb MH Transl Oncol 2018 Feb 11 2 292-299