A major and longstanding interest of our laboratory is the delineation of the cellular and molecular mechanisms by which growth hormone (GH) regulates body growth and metabolism. GH is the primary hormone responsible for longitudinal body growth; it also regulates metabolism and other body functions. The GH receptor is a member of the cytokine family of cell surface receptors. Our laboratory was one of the first to show that cytokines activate JAK family kinases and helped delineate the JAK-Stat pathway for cytokine receptors, the primary signaling pathway for more than 25 different ligands. We showed that binding of GH to its receptor rapidly activates the GH receptor-associated tyrosine kinase JAK2 and the Stat transcription factors. We have used a variety of approaches to identify multiple additional signaling proteins and pathways that are initiated by GH as a consequence of its activation of JAK2. We also study how JAK2 is activated in response to ligand binding and subsequently deactivated. Because JAKs are key signaling proteins for multiple cytokines important for multiple body functions, our studies are relevant to many diseases and syndromes, including short stature, metabolic syndrome, obesity, myeloproliferative disorders, multiple cancers and diseases involving the immune system (e.g. rheumatoid arthritis, severe combined immunodeficiency disease [SCID]).

One JAK2 binding protein identified by our lab is the scaffolding protein SH2B1. SH2B1 is recruited to activated JAK2 in response to GH and the satiety hormone leptin. SH2B1 is also recruited to a variety of activated receptor tyrosine kinases, including the receptors for multiple neurotrophins, insulin, and insulin-like growth factor. Mice lacking SH2B1 are obese and insulin-resistant. We have recently initiated a collaboration with Dr. Farooqi’s group at the University of Cambridge, England. The Farooqi lab has identified patients with point mutations in SH2B1. These patients exhibit severe childhood obesity, insulin resistance, and sometimes maladaptive behavior and short stature. We are currently investigating at the cellular and molecular levels how SH2B1 affects such a diverse array of important body functions. We have implicated SH2B1 in cell motility and nerve growth factor-dependent neuronal differentiation, and shown that SH2B1 cycles between the plasma membrane and the nucleus. We have shown that the human mutations disrupt at least some of these functions of SH2B1. We have also determined that phosphorylation of specific residues in SH2B1 dramatically alters the subcellular localization and function of SH2B1, and that the different isoforms of SH2B1 exhibit differences in function. Our laboratory uses standard immunological, biochemical, recombinant DNA, and imaging techniques, phosphopeptide mapping, phosphoproteomics, microarrays, confocal microscopy, total internal reflection fluorescence microscopy (TIRFM), and fluorescence recovery after photobleaching (FRAP). Animal studies looking at the function of SH2B1 isoforms in the brain are also being initiated.