Download Rohatgi Lab - Stanford Biochemistry

Rohatgi Lab
Cell Biology of Signal Transduction in Development and Disease
Background
Developmental signaling pathways, initially studied for their roles in embryogenesis, have been
implicated in adult organ regeneration, stem-cell function, and cancer. Our long term goal is to
understand the spatial, temporal, and biochemical regulation of these pathways as a step towards
exploiting them for human therapeutics.
Questions
1. Biochemical Mechanisms of Hedgehog Signaling.
The Hedgehog pathway controls the development of most organs and has been shown to drive a
variety of adult cancers. Anti-Hedgehog drugs are entering clinical trials in humans and hold great
promise in oncology and regenerative medicine. We seek a biochemical understanding of the steps
in Hedgehog signaling and hope to translate this information into new therapeutic and diagnostic
strategies for human cancer patients.
2. Signal transduction at the primary cilium.
Primary cilia are solitary hair-like projections found on most cells in our bodies. Driven by findings
from human genetics, primary cilia have emerged as critical hubs for signal transduction. Defects in
cilia cause human disorders ranging from congenital malformations to obesity. Hedgehog is one of
many of signaling pathways that is orchestrated at this poorly understood organelle. We want to
understand how protein function is regulated at this biochemical compartment to facilitate signal
transduction.
Systems
1. Cultured cells.
2. Mice.
3. Primary human tissue samples.
Approaches
Our philosophy holds that the integration of bulk methods such as biochemical reconstitution and
protein purification with single cell methods, such as microscopy with innovative optical and
chemical probes, provides a powerful approach to problems in signal transduction.
Primary cilium: small but elaborate. The inset shows a typical
fibroblast in culture with a cilium ( ~5μM x 0.5μM). Proteins
targeted to cilia are carried by transport complexes that move
the proteins towards the tip of the cilium (red path) or back
towards the base of the cilium (green path) for exit.
Protein trafficking at cilium. The Hedgehog receptor
Patched is highly concentrated in the ciliary membrane (left).
After ligand (Shh) addition, the Hedghog pathway protein
Smo translocates to primary cilia. The biochemical regulation
of these signal-induced changes in localization is unknown.