Salk Institute for Biological Studies


Greg  Lemke

Greg Lemke

Molecular Neurobiology Laboratory
Françoise Gilot-Salk Chair



The Regulatory Logic of Signaling

Our group uses molecular genetics to study the regulation of signaling networks that control nervous system development and immune system function. Much of our current work is focused on signaling through receptor tyrosine kinases (RTKs) of the TAM and Eph receptor families.

We are interested in how expression gradients of Eph receptors are established across fields of developing neurons, and how these interacting RTK gradients function during the topographic wiring of the eye to the brain. Current efforts are directed toward the analysis of a set of transcription factors (Vax proteins) that integrate the activities of the Sonic hedgehog and Wnt morphogen gradients that initially specify Eph receptor gradients in the embryonic nervous system.

The systems biology of the TAM RTKs in the mature immune system is a second major focus of the lab. These receptors, and their integration and regulation of the innate immune response, were both initially described by our group. We are currently studying the role that TAM RTKs play in the maintenance of cellular homeostasis in macrophages, dendritic cells, and B cells. We are particularly interested in the role that dysregulation of the TAM signaling network plays in (a) the development of autoimmune diseases such as Lupus, Multiple Sclerosis, and Rheumatoid Arthritis, and (b) the course of infection by influenza, West Nile, and Dengue viruses.

"In biology, the ability to turn something on is always coupled with a mechanism to turn it off. In the absence of this regulation, a biological system is akin to the 'Sorcerer's Apprentice,' who set in motion a chain of events over which he had no control. TAM receptors play this role in the immune system: They regulate the innate immune responses to bacteria, viruses and other pathogens, ensuring that it is strong enough to defeat these threats, but not so strong that it endangers the host."

Antigen-presenting cells or APCs, which provide the body's first line of defense against disease-causing bacteria and viruses, are constantly on the prowl in search of pathogens. When they encounter foreign invaders, they unleash a "cytokine storm"—a wave of chemical messengers that jumpstart the T and B cell response. When the invaders have been successfully vanquished, the APCs need to shut down; otherwise, chronic inflammation ensues, overwhelming the regulatory mechanisms that normally distinguish "self" from "non-self," leading to autoimmune diseases such as lupus and rheumatoid arthritis. Lemke and his team explored how the socalled TAM receptors (Tyro3, Axl, Mer) in mice stop the immune system from mounting an out-of-control, destructive inflammatory response against invading pathogens. When receptors studded on the surface of patrolling APCs encounter a pathogen, the cells release an initial burst of cytokines, which is then amplified in a second stage through cytokine receptors. But this same activation pathway trips the fuse that is designed to prevent the inflammatory response from spiraling out of control.

The researchers found that a stimulator of inflammation—the type 1 interferon receptor (IFNAR)—turns on the expression of Axl, a TAM receptor. Axl and IFNAR then physically bind together and activate SOCS genes, whose products are potent inhibitors of pro-inflammatory signaling pathways. Without TAM receptors, they discovered, the APCs never shut down after their initial activation, but remain in a state of red alert.

Knowing how important TAM receptors are to the control of inflammation in mice will not only aid our understanding of human immune system disorders but might enable researchers to manipulate the switch in ways that could be clinically beneficial. For example, a drug that inhibited TAMs in the short term could be given along with a therapeutic vaccine in order to help the body mount a better immune response. Conversely, it may be possible to engage the TAMs early in an immune reaction to treat chronic autoimmune diseases such as lupus.

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