Assistant Professor of Oncological Sciences
A.B. Harvard University
Ph.D. University of California, San Francisco
Ben Myers' Lab Page
Ben Myers' PubMed Literature Search
Molecular Biology Program
Biological Chemistry Program
Signaling across the membrane in development and cancer: Hedgehog, Wnt,
primary cilium, membrane proteins / lipids, second messengers
Our lab studies how cells communicate with one another, a process that regulates nearly all aspects of animal development and, when damaged, leads to cancer and other diseases. Transmembrane proteins play critical roles in cell-cell communication by transmitting cell fate signals from the cell's external environment to its interior. In this regard, transmembrane proteins serve as gatekeepers whose initial decisions ultimately determine a cell fate pathway’s final activity state. But despite their important physiological roles, we do not understand how transmembrane proteins are regulated to produce proper amounts of downstream signals at the right times and places within the organism. This has limited our ability to control cell fate signaling therapeutically. The Myers lab is studying the biochemical and biophysical mechanisms that regulate transmembrane protein activity in cell fate pathways. A better understanding of these processes will help us develop therapeutic strategies to manage a broad array of birth defects, regenerative disorders, and malignancies.
Hedgehog Signal Transduction
Much of our work focuses on the Hedgehog (Hh) signaling pathway, a quintessential cell fate specification cascade that provides an experimentally accessible model to study transmembrane signaling in development and disease. Hh is a major player in embryogenesis and regeneration, directing the patterning of nearly every vertebrate organ. Insufficient Hh signaling is linked to common birth defects, while inappropriate pathway activity drives several widespread cancers. Yet surprisingly, the critical biochemical events regulating Hh signaling at the membrane remain largely unknown. Our goal is to reveal the molecular basis by which cells respond to Hh signals -- a central mystery in developmental and cancer biology. We are developing optical, biochemical, and electrical sensors to monitor key Hh signal transduction events as they unfold in real-time. By using these sensors to study key Hh pathway steps in cell-based and in vitro experimental systems, we will gain a deep understanding of the underlying transduction mechanism. In parallel, we will use the tools and insights from these simplified experimental preparations to study Hh signaling in more native cellular and organismal models.
The Primary Cilium
Apart from its roles in development and cancer, Hh also serves as a powerful model for signal transduction within the vertebrate primary cilium. The primary cilium is a tiny microtubule-based membrane protrusion critical to Hh as well as multiple G-protein-coupled receptor (GPCR) pathways in the nervous, cardiovascular, and musculoskeletal systems. Mutations in ciliary components affect numerous aspects of human physiology and can profoundly influence cancer progression. However, the mechanistic basis for such defects is generally not understood because ciliary signaling pathways are often studied with indirect methods that are unable to detect second messenger dynamics within this organelle. We will shed light on this question by elucidating the underlying physiology of primary cilia – a fascinating area of biology that remains largely unexplored.
How Transmembrane Signaling Specifies Cellular Identity
Beyond Hh and the primary cilium, we aim to apply our unique mindset and approaches to a broad range of signaling pathways relevant to human health and physiology. Within all of these contexts, membrane proteins and lipids play indispensable roles in determining cellular identity in animals and are often misregulated in cancer. Nevertheless, these molecules remain understudied due to a lack of appropriate tools. Our research on Hh and ciliary pathways will provide a blueprint to tackle other cell fate pathways whose membrane signaling mechanisms are poorly characterized. These studies will dramatically increase our understanding of an entire class of critical regulatory events that specify cell fate. They will also help us engineer better drugs to effectively control transmembrane protein activity while minimizing issues like drug resistance and side effects.
- Myers, B. R.*^, Neahring, L.*, Zhang, Y., Roberts, K. R., Beachy, P. A.^. Rapid, direct activity assays for Smoothened reveal
Hedgehog pathway regulation by membrane cholesterol and extracellular sodium. Proc Nat Acad Sci10.1073/pnas.1717891115 (2017) (* = first author; ^ = corresponding author). pdf
- Commentary by Blassberg and Briscoe in Dev Cell: pdf
- Sweeney, R.T.*, McClary, A.C.*, Myers, B.R.*, Biscocho, J.*, et al. Identification of Recurrent SMO and BRAF Mutations in Ameloblastomas. Nat Gen46(7):722-5 (2014). (* = first author)
- Myers, B. R., Sever, N., Chong, Y. C., Kim, J., Belani, J. D., Rychnovsky, S., Bazan, J. F., Beachy, P. A. Hedgehog Pathway Modulation by Multiple Lipid Binding Sites on the Smoothened Effector of Signal Response. Dev Cell 26(4):346-57 (2013).
- Myers, B. R., Sigal, Y. M., Julius, D. Evolution of Thermal Response Properties in a Cold-Activated TRP Channel. PLoS ONE 4(5): e5741. doi:10.1371/journal.pone.0005741 (2009).
- Prober, D. A., Zimmerman, S., Myers, B. R., McDermott, B. M., Caron, S., Rihel, J., Kim, S., Kettleborough, R. N. W., Stemple, D. L., Solnica-Krezel, L., Julius, D., Hudspeth, A. J., Schier, A. F. Zebrafish TRPA1 Channels are Required for Behavioral Responses to Mustard Oil but not for Thermosensation or Mechanosensory Hair Cell Function. J Neurosci 28(40):10102-10 (2008).
- Myers, B. R., Saimi, Y., Kung, C., Julius, D. Multiple Unbiased Prospective Screens Identify TRP Channels and their Conserved Gating Elements. J Gen Physiol. 132(5): 481-6 (2008).
- Myers, B. R., Bohlen, C., Julius, D. A Yeast Genetic Screen Reveals a Critical Role for the Pore Helix Domain in TRP Channel Gating. Neuron 58(3):362-73 (2008).
- Myers, B. R., Julius. D. TRP Channel Structural Biology: New Roles for an Old Fold. Neuron 54(6):847-50 (2007).
- Desai, B. N., Myers, B. R., Schreiber, S. L. FKBP12-rapamycin associated protein associates with mitochondria and senses osmotic stress via an intermediate mitochondrial dysfunction. Proc. Natl. Acad. Sci. USA 99(7):4319-24 (2002).