"In Praise of Signal Transduction: Discovery of Pathways Affecting Growth, Obesity and Cancer"

The ability to correctly coordinate biochemical signaling events is essential for life. Signal transduction occurs when a hormone in the circulation or an extracellular ligand binds to a specific receptor protein and triggers a biochemical chain of signaling events inside the cell. Depending on the cell and the ligand, the chain of events alters the cell's metabolism, shape, gene expression, and/or ability to divide. We asked how growth hormone (GH) initiates cellular responses that ultimately result in a coordinated increase in body growth and altered fat and carbohydrate metabolism. We hypothesized that GH might function like the small group of growth factors then known to activate a tyrosine kinase built into their receptors. Instead, we found a new paradigm in which GH activates a separate tyrosine kinase (JAK2) that is recruited to the GH receptor. This paradigm was found to apply to a whole group of receptors that bind proteins involved in immune function, appetite suppression, hematopoiesis, and nerve function. We next determined that Stat transcription factors that regulate gene expression are phosphorylated and activated by JAK2. JAK2 and Stats were found to be essential for GH to regulate body height and metabolism. JAKs and Stats are now known to also cause a variety of cancers when activated abnormally. Much of our work has focused on identifying cellular targets of JAK2. One such protein is the scaffold protein SH2B1. SH2B1 is recruited to activated JAK2 and is critical for GH-dependent changes in the actin cytoskeleton and cell motility. SH2B1 is recruited to a variety of receptors implicated in neuronal function and body metabolism. Recently, human patients have been identified that carry genetic mutations in SH2B1. In addition to decreased adult height, these patients exhibit severe early onset childhood obesity and insulin resistance. Thus, by asking the simple question of how GH acts at the cellular and molecular level, we have identified proteins that regulate not just height, but also play critical roles in body weight regulation and multiple cancers.