The Design Principles of Cellular Signaling Systems

• Signal transduction
• Systems biology
• Synthetic biology
• Protein interactions
• Scaffold and switch proteins
• Protein modules
• Network modules
• Evolution & optimization of signaling proteins and networks
• Design principles of spatial and temporal control networks in cells
• Immune signaling and engineering therapeutic immune cells
• Optogenetics: control & interrogation of cellular processes

Fundamental Questions

Living cells process vast amounts of environmental information to generate sophisticated responses such as movement, growth and differentiation. Such decisions are made by complex networks of signal transduction proteins. One of the most challenging problems in modern biology is understanding how these networks of proteins act to carry out these remarkable behaviors.

Much evidence suggest that complex signaling systems can be understood, in part, through the framework of modularity and hierarchical organization. Diverse signaling proteins are composed of conserved modular domains - some that carry out catalytic functions and others that carry out regulatory or interaction functions. It appears that combinations of these domains into proteins/complexes yields elemental signaling nodes, and these nodes are hierarchically organized simple network or circuit modules that carry out elemental processing functions. Thus, the seemingly impossibly complex networks in a cell can perhaps be understood by understanding the principles by which signaling modules at different levels are hierarchically organized.

Thus we are using a variety of approaches to ask the following range of general questions:

1. How do molecular signaling systems program complex cellular behaviors?
2. What are the mechanisms of signaling proteins and complexes - especially scaffold or switch proteins?
3. How do signaling proteins and networks evolve?
4. How are simpler proteins combined and organized to form proteins and networks that can achieve more complex decisions?
5. How do these networks robustly program complex spatial/temporal responses?
6. Can we systematically build new signaling circuits or modify cellular behavior?
7. Can we develop new tools & approaches to understand and to build signaling networks?
8. Can we engineer cells with new, useful behaviors (therapeutic cells, biotechnology production)?

Methods

To address these questions, we integrate the complementary approaches of reverse engineering (dissecting natural systems) and synthetic biology (using natural modules to build new or modified functions). We use a broad range of techniques including:

• biochemistry/structural biology
• yeast genetics
• microscopy
• optogenetics
• synthetic biology
• immunology

Current Project Areas

Some current project areas are listed below:

• structure, mechanism and cell biology of scaffold proteins: how they wire cellular signaling networks
• programming spatial self-organization in cells and multicellular structures
• programming temporal control in cells using post-translational circuits (phosphorylation/GTPase)
• combinatorial circuit design and in vitro evolution
• exploring design principles of circuit modules through computational enumeration and synthetic biology
• evolution of phosphotyrosine signaling and multicellularity
• optogenetic approaches to control and probe cellular signaling networks
• optimization of cellular stress responses behaviors
• engineering therapeutic immune cells (T cells)

To learn more about specific projects, browse the Lim Lab publications or visit the pages of the Lim Lab members.

If you are interested in joining the lab, please click here. People from diverse backgrounds including cell & molecular biology, biophysics, structural biology, immunology, neurobiology, development, chemistry, engineering, mathematics and physics are welcome.

We are a part of several multi-institutional centers including the Cell Propulsion Lab (an NIH Nanomedicine Development Center), the NSF Synthetic Biology Engineering Research Center (SynBERC), and the UCSF Center for Systems and Synthetic Biology (an NIGMS National Systems Biology Center).