We study protein kinase signal-transduction mechanisms, and how kinase structures lead to cell biological functions. We are particularly focused on the contributions of ERK MAP kinases in development and neuroendocrine cancers, regulation of and pathways controlled by WNK protein kinases and actions of TAO protein kinases outside of their actions upstream of MAPK pathways.
ERK1/2
Mitogen-activated protein kinases (MAPKs) are universal elements of signaling processes in all cells. 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 Noonan Syndrome and other Rasopathies to diabetes to very common contributions to cancer. We study how mutations in and altered regulation of ERK1/2 shift the balance in numerous cell functions in the nucleus, cytoplasm and cytoskeleton and membrane compartments. Understanding ERK1/2 feedback and inactivation mechanisms are also key elements impacting their functions.
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 suppressed 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. In parallel we are interested in understanding why and how ERK2 mutations are categorized as gain- or loss-of-function mutations, particularly as several characterized mutations actually have features of both. In what contexts are the gains or losses dominating phenotypes?
WNK
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 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 and it cooperates with transforming growth factor beta in angiogenesis. 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 the importance of WNK1 in cancer. Most recently we have found that WNK1 is activated by the mechanosensitive ion channel Piezo1 in the endothelium and other cell types.
TAOKs
We originally identified TAO kinases as MAP3Ks upstream of the p38 MAPK pathway, for example in response to genotoxic stress. TAOs have many other fascinating functions. The single TAO in Schisotosomes is required for their survival. TAOK2 mediates export of a spectrum of viral RNAs from the nucleus and is also involved in remodeling dendritic spines in neurons. We are identifying novel TAO substrates involved in some of these physiological functions.