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
- OSR1 regulates a subset of inward rectifier potassium channels via a binding motif variant.
- Taylor CA, An SW, Kankanamalage SG, Stippec S, Earnest S, Trivedi AT, Yang JZ, Mirzaei H, Huang CL, Cobb MH Proc. Natl. Acad. Sci. U.S.A. 2018 Mar
- Enteroid Monolayers Reveal an Autonomous WNT and BMP Circuit Controlling Intestinal Epithelial Growth and Organization.
- Thorne CA, Chen IW, Sanman LE, Cobb MH, Wu LF, Altschuler SJ Dev. Cell 2018 Mar 44 5 624-633.e4
- Differential abundance of CK1a provides selectivity for pharmacological CK1a activators to target WNT-dependent tumors.
- Li B, Orton D, Neitzel LR, Astudillo L, Shen C, Long J, Chen X, Kirkbride KC, Doundoulakis T, Guerra ML, Zaias J, Fei DL, Rodriguez-Blanco J, Thorne C, Wang Z, Jin K, Nguyen DM, Sands LR, Marchetti F, Abreu MT, Cobb MH, Capobianco AJ, Lee E, Robbins DJ Sci Signal 2017 Jun 10 485
- Multistep regulation of autophagy by WNK1.
- Gallolu Kankanamalage S, Lee AY, Wichaidit C, Lorente-Rodriguez A, Shah AM, Stippec S, Whitehurst AW, Cobb MH Proc. Natl. Acad. Sci. U.S.A. 2016 Dec 113 50 14342-14347
- Chemoattractant concentration-dependent tuning of ERK signaling dynamics in migrating neutrophils.
- Zhang ER, Liu S, Wu LF, Altschuler SJ, Cobb MH Sci Signal 2016 Dec 9 458 ra122
- Insulin promoter-driven Gaussia luciferase-based insulin secretion biosensor assay for discovery of ß-cell glucose-sensing pathways.
- Kalwat MA, Wichaidit C, Nava Garcia AY, McCoy MK, McGlynn K, Hwang IH, MacMillan JB, Posner BA, Cobb MH ACS Sens 2016 Oct 1 10 1208-1212
- Amino Acids Regulate mTORC1 by an Obligate Two-Step Mechanism.
- Dyachok J, Earnest S, Iturraran EN, Cobb MH, Ross EM J. Biol. Chem. 2016 Sep
- ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs.
- Borromeo MD, Savage TK, Kollipara RK, He M, Augustyn A, Osborne JK, Girard L, Minna JD, Gazdar AF, Cobb MH, Johnson JE Cell Rep 2016 Jul
- Phosphorylation or Mutation of the ERK2 Activation Loop Alters Oligonucleotide Binding.
- McReynolds AC, Karra AS, Li Y, Lopez ED, Turjanski AG, Dioum E, Lorenz K, Zaganjor E, Stippec S, McGlynn K, Earnest S, Cobb MH Biochemistry 2016 Mar 55 12 1909-17
- Isoxazole Alters Metabolites and Gene Expression, Decreasing Proliferation and Promoting a Neuroendocrine Phenotype in ß-Cells.
- Kalwat MA, Huang Z, Wichaidit C, McGlynn K, Earnest S, Savoia C, Dioum EM, Schneider JW, Hutchison MR, Cobb MH ACS Chem. Biol. 2016 Feb