The members of the Cobb lab study the signal-transduction mechanisms of protein kinases, and how kinase structures lead to cell biological functions.  

We are particularly focused on the contributions of ERK MAP kinases to pancreatic beta cell function and to lung cancers, and on the actions of WNK protein kinases.


Mitogen-activated protein kinases (MAPKs) are universal elements of signaling pathways. ERK2 has long served as a prototype to define properties of MAPKs and their cascades. ERK2 and/or the closely related protein kinase ERK1 are required not only for embryogenesis, differentiation, and proliferation, but also for the everyday functions of differentiated cells, e.g., changes in membrane permeability, long term potentiation, and cell type-specific transcription.

The misregulated or otherwise inappropriate functions of ERK1/2 contribute to diseases ranging from cardio-facio-cutaneous syndrome to diabetes to cancer. We study how ERK1/2, essential, ubiquitous signaling proteins, act with ligand-dependent specificity. We are particularly interested in mechanisms of chromatin and DNA interactions and chromatin-bound functions, regulation of microtubule depolymerizing kinesins, control of pancreatic beta cell function, and how ERK1/2 are inactivated with specificity.

Small Cell Lung Cancer (SCLC)

An important goal is to understand how ERK1/2 contribute to tumor growth in cancer. The functions of ERK1/2 are often usurped in cancers, such as non-small cell lung cancer (NSCLC), to support proliferation, migration, and survival of tumors. On the other hand, ERK1/2 are inactivated in small cell lung cancer (SCLC), a neuroendocrine cancer, as they have been shown to inhibit SCLC survival. We are exploring these and other SCLC survival mechanisms that might be targeted therapeutically.


We identified the protein kinase WNK1 (With No lysine (K) 1) by low stringency cloning, determined the structure of its uniquely organized catalytic domain, demonstrated its sensitivity to osmotic state, and identified regulation of primary downstream protein kinases and ion transporters.  To date, ion transport has been the WNK1 focal point because mutations that increase its expression in kidney cause a rare form of hypertension.  Whole-body and endothelial-selective disruption of the mouse WNK1 gene by Chou-Long Huang (Internal Medicine, UTSW) produce the same phenotype: death at E11-12 due to failed remodeling of the embryonic vasculature.  These results reveal an absolute developmental requirement for WNK1 in the endothelium.  By scrutinizing endothelial cells in two- and three-dimensional assays, we found that WNK1 is required for migration, directional movement, forming oriented cell-cell contacts, and sprouting from a formed endothelial cord or tube.  At a molecular level, WNK1 is required for expression of the mesenchymal transcription factor Slug (SNAI2) and for small GTPase-mediated actin dynamics, to initiate cell movement from an otherwise differentiated tissue.  We have also determined other WNK1-regulated events that are important for its unique biological actions. We are studying WNK1 signaling mechanisms crucial for vessel restructuring and repair, its actions on vesicular trafficking and cell migration, and the importance of WNK1 in cancer.