Our laboratory studies the molecular machinery used by cells to interpret extracellular signals and transduce them to the nucleus to effect changes in gene expression. This process is of fundamental biological importance. The accurate response to extracellular signals results in a cell's decision to proliferate, differentiate, or die, and it is critical for normal development and physiology. The disregulation of this machinery underlies the unwarranted expansion or destruction of cell numbers that occurs in human diseases like cancer, autoimmunity, hyperinflammatory states, and neurodegenerative disease.

Currently, we study signaling pathways that are important in innate immunity, adaptive immunity, and in cancer, paying particular attention to pathways that regulate the activity of the pleiotropic transcription factor NF-kB. We are interested in these broad questions:

• What are the biochemical mechanisms of signal transduction?
• How is the input-output specificity determined so that each particular ligand or extracellular cue induces the appropriate cellular response?
• How does the molecular specificity at the atomic level underlie biological specificity at the organismal level?
• How are signaling pathways disregulated in human disease and can we use this knowledge to develop new therapeutics?
• Can we use our understanding of signaling mechanisms to design novel, artificial signaling circuits for research and therapeutic purposes, for example, to control cell fate?

Examples of current projects:

The biochemistry of antigen receptor signaling in B and T lymphocytes.
The activation of NF-kB by antigen receptor engagement is a critical requirement for the activation of lymphocytes in the adaptive immune response. Using a novel expression cloning strategy designed to isolate molecules that signal to NF-kB in lymphocytes, we cloned CARD11, a multiprotein adaptor molecule and member of the MAGUK family of signaling proteins. We demonstrated that CARD11 plays a pathway-specific, factor-specific role in the activation of NF-kB downstream of T cell receptor signaling (Pomerantz, Denny, and Baltimore, 2002). We are currently investigating the biochemical mechanisms by which CARD11 transduces signals from the T cell receptor to NF-kB.

Expression cloning of signaling molecules that regulate NF-kB, NFAT, and other transcription factors.
We have used our expression cloning strategy (Pomerantz, Denny, and Baltimore, 2002) to clone several novel signaling molecules that signal the activation of the NF-kB or NFAT transcription factors. We will study their biological roles and characterize their mechanisms of action. We are also investigating whether our protocol is adaptable for the isolation of signaling molecules that regulate other transcription factors that influence the decision to proliferate, differentiate, or die, and that are disregulated in human disease.

Design of novel signal transduction pathways for cell engineering.
We are interested in testing our understanding of signal transduction by applying mechanistic insights toward the design of novel artificial cellular circuits. Our goal is to develop heterologous circuitry that would provide new tools for controlling gene expression to be used in biological research and to engineer cell fate decisions in novel therapeutic approaches.