Growth Hormone Regulation of SH2B1
Principal Investigator: Christin Carter-Su
Abstract: DESCRIPTION (provided by applicant): Exciting recent genetic studies implicate the scaffold protein SH2B1 in human disease. Human mutations in SH2B1 are associated with severe early onset obesity with disproportionately severe insulin resistance, impaired brain development, and, in some cases, short stature. This phenotype (strikingly similar to that of SH2B1-/- mice) is consistent with SH2B1 being a signaling molecule for multiple ligands, including growth hormone (GH), leptin, and insulin. SH2B1 is recruited to JAK2 and is a critical component in GH regulation of the actin cytoskeleton, a prerequisite for cellular proliferation, differentiation and migration. However, the mechanism by which SH2B1 facilitates GH-induced changes in the actin cytoskeleton remains largely unknown. The long-term goal is to understand the mechanism by which SH2B1 contributes to the function of GH and other ligands, and to gain insight into unrecognized cellular actions of GH;new functions of SH2B1;and how scaffold proteins such as SH2B1 move highly regulated and dynamic complexes from membrane-bound receptors to multiple, often remote, sites in the cell (e.g., focal adhesions, lamellipodia, cytoplasm, nucleus). The objective of the current proposal is to understand how SH2B1 regulates assembly and movement of "signaling complexes" and whether dysregulation of these functions contributes to defects in cellular function and ultimately human obesity, insulin-resistance, neurologic disorders, and suppressed growth. The central hypothesis is that SH2B1 facilitates the formation and/or movement of SH2B1 "signaling complexes" to specific locations in the cell (e.g., pm, lamellipodia, cytoplasm, nucleus) in response to GH. These functions of SH2B1 enhance GH regulation of the actin cytoskeleton, GH-induced motility, and GH responses in the nucleus. They are critical to normal human physiology, such that their impairment due to mutation contributes to the dramatic phenotype observed in human patients. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Elucidate the mechanism by which SH2B1 reversibly localizes to the plasma membrane, cytosol and nucleus. 2) Determine the role of SH2B1 in regulating GH-induced changes in the actin cytoskeleton, cell motility, and trafficking of proteins between intracellular compartments. 3) Determine the functional consequences of mutations in SH2B1 associated with human disease. Experiments will use a combination of biochemical, immunologic, cell biology, and imaging techniques standard in the lab. State-of-the-art microscopes, photoactivable probes, proteomics, cell lines and both primary macrophages and MEFs from SH2B1-/- mice, will also be used. The concept that the nuclear localization signal of SH2B1 is a dual function motif that mediates both nuclear import and plasma membrane binding that is regulated by phosphorylation of nearby serines is innovative. The proposed research is significant because it will provide insight into the role of SH2B1 in the function of GH and the numerous other ligands (e.g., leptin, insulin, nerve growth factor) that utilize SH2B1 as a signaling protein. PUBLIC HEALTH RELEVANCE: These studies will provide insight into the role of a multifunctional adapter protein SH2B1 in the function of growth hormone and the many other cytokines, hormones and growth factors (e.g. leptin, insulin, nerve growth factor) that use SH2B1 to mediate their effects in cells. Such insight is critical to our understanding on how growth hormone brings about its well known diverse effects in the body, including body growth and metabolism, and other SH2B1 activating ligands contribute to, prevent and/or alleviate symptoms of a variety of diseases including obesity, various cancers, diabetes, multiple sclerosis, and diseases of the immune system.
Funding Period: 1999-07-01 - 2015-08-31
more information: NIH RePORT
- Binding of SH2-B family members within a potential negative regulatory region maintains JAK2 in an active stateJason H Kurzer
Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109 0622, USA
Mol Cell Biol 26:6381-94. 2006..Rather, they most likely induce or stabilize an active conformation of JAK2...
- Human SH2B1 mutations are associated with maladaptive behaviors and obesityMichael E Doche
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109 5622, USA
J Clin Invest 122:4732-6. 2012..We conclude that SH2B1 plays a critical role in the control of human food intake and body weight and is implicated in maladaptive human behavior...
- The SH2B1 adaptor protein associates with a proximal region of the erythropoietin receptorMojib Javadi
Ontario Cancer Institute, Campbell Family Cancer Research Institute, Toronto, Ontario M5G 2M9, Canada
J Biol Chem 287:26223-34. 2012..In the absence of SH2B1, we observe enhanced activation of signaling pathways downstream of the EPO-R, indicating that SH2B1 is a negative regulator of EPO signaling...
- Identification of SH2B1β as a focal adhesion protein that regulates focal adhesion size and numberNathan J Lanning
University of Michigan Medical School, Ann Arbor, MI 48109 5622, USA
J Cell Sci 124:3095-105. 2011..The finding that phosphorylation of SH2B1β increases the number of focal adhesions suggests a mechanism for the stimulatory effect on cell motility of SH2B1β...
- Phosphorylation controls a dual-function polybasic nuclear localization sequence in the adapter protein SH2B1β to regulate its cellular function and distributionTravis J Maures
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109 5622, USA
J Cell Sci 124:1542-52. 2011....
- Nucleocytoplasmic shuttling of the adapter protein SH2B1beta (SH2-Bbeta) is required for nerve growth factor (NGF)-dependent neurite outgrowth and enhancement of expression of a subset of NGF-responsive genesTravis J Maures
Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109 5622, USA
Mol Endocrinol 23:1077-91. 2009....
- SH2B1beta (SH2-Bbeta) enhances expression of a subset of nerve growth factor-regulated genes important for neuronal differentiation including genes encoding urokinase plasminogen activator receptor and matrix metalloproteinase 3/10Linyi Chen
Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109 0622, USA
Mol Endocrinol 22:454-76. 2008....
- SH2B1 enhances leptin signaling by both Janus kinase 2 Tyr813 phosphorylation-dependent and -independent mechanismsZhiqin Li
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109 0622, USA
Mol Endocrinol 21:2270-81. 2007..SH2B1-IRS1 interaction facilitates IRS1 phosphorylation by recruiting IRS1 to JAK2 and/or by protecting IRS1 from dephosphorylation, thus specifically enhancing leptin stimulation of the phosphatidylinositol 3-kinase pathway...
- Adapter protein SH2-Bbeta stimulates actin-based motility of Listeria monocytogenes in a vasodilator-stimulated phosphoprotein (VASP)-dependent fashionMaria Diakonova
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
Infect Immun 75:3581-93. 2007....
- Recent advances in growth hormone signalingNathan J Lanning
Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, MI 48109 0622, USA
Rev Endocr Metab Disord 7:225-35. 2006..This review will highlight some of these findings, many of which are unexpected and some of which challenge previously held beliefs about the mechanisms of GH signaling...
- Multiplexed detection of protein-peptide interaction and inhibition using capillary electrophoresisPeilin Yang
Department of Chemistry, University of Michigan, 930 North University, Ann Arbor, Michigan 48109 1055, USA
Anal Chem 79:1690-5. 2007..It is concluded that high-speed CE has the potential for multiplexed screening of drugs that disrupt protein-protein interactions...
- SH2B1 (SH2-B) and JAK2: a multifunctional adaptor protein and kinase made for each otherTravis J Maures
Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109 0662, USA
Trends Endocrinol Metab 18:38-45. 2007..Thus, knockout mice support a role for SH2B1 as a positive regulator of JAK2 signaling pathways initiated by leptin, as well as of pathways initiated by insulin and, potentially, by insulin-like growth factor I...
- Phosphorylation of the adaptor protein SH2B1β regulates its ability to enhance growth hormone-dependent macrophage motilityHsiao Wen Su
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
J Cell Sci 126:1733-43. 2013..g. as a result of phosphorylation of serines 161 and 165)...
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