Growth Hormone Regulation of SH2B1

Summary

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

Top Publications

  1. pmc Binding of SH2-B family members within a potential negative regulatory region maintains JAK2 in an active state
    Jason 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
  2. pmc Human SH2B1 mutations are associated with maladaptive behaviors and obesity
    Michael 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
  3. pmc The SH2B1 adaptor protein associates with a proximal region of the erythropoietin receptor
    Mojib Javadi
    Ontario Cancer Institute, Campbell Family Cancer Research Institute, Toronto, Ontario M5G 2M9, Canada
    J Biol Chem 287:26223-34. 2012
  4. pmc Identification of SH2B1β as a focal adhesion protein that regulates focal adhesion size and number
    Nathan J Lanning
    University of Michigan Medical School, Ann Arbor, MI 48109 5622, USA
    J Cell Sci 124:3095-105. 2011
  5. pmc Phosphorylation controls a dual-function polybasic nuclear localization sequence in the adapter protein SH2B1β to regulate its cellular function and distribution
    Travis 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
  6. pmc 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 genes
    Travis 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
  7. pmc 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 3/10
    Linyi 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
  8. ncbi SH2B1 enhances leptin signaling by both Janus kinase 2 Tyr813 phosphorylation-dependent and -independent mechanisms
    Zhiqin Li
    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109 0622, USA
    Mol Endocrinol 21:2270-81. 2007
  9. pmc Adapter protein SH2-Bbeta stimulates actin-based motility of Listeria monocytogenes in a vasodilator-stimulated phosphoprotein (VASP)-dependent fashion
    Maria Diakonova
    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
    Infect Immun 75:3581-93. 2007
  10. ncbi Recent advances in growth hormone signaling
    Nathan 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

Research Grants

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
  2. DEVELOPMENTAL BIOLOGY OF HUMAN ERYTHROPOIESIS
    Stuart H Orkin; Fiscal Year: 2013
  3. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
  4. PATHOPHYSIOLOGY OF THE ENDOTHELIUM
    Francis W Luscinskas; Fiscal Year: 2013
  5. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
  6. CSHL CANCER CENTER SUPPORT GRANT
    BRUCE W STILLMAN; Fiscal Year: 2013
  7. IBD and Mucosal Inflammation, Immunology, and Microbiology of the GI Tract
    Eugene B Chang; Fiscal Year: 2013
  8. TSH RECEPTOR MULTIMERIZATION
    TERRY FRANCIS DAVIES; Fiscal Year: 2013
  9. Mechanisms of Integrin-Mediated Costimulation in T Cells
    Stephen C Bunnell; Fiscal Year: 2013
  10. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013

Detail Information

Publications13

  1. pmc Binding of SH2-B family members within a potential negative regulatory region maintains JAK2 in an active state
    Jason 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...
  2. pmc Human SH2B1 mutations are associated with maladaptive behaviors and obesity
    Michael 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...
  3. pmc The SH2B1 adaptor protein associates with a proximal region of the erythropoietin receptor
    Mojib 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...
  4. pmc Identification of SH2B1β as a focal adhesion protein that regulates focal adhesion size and number
    Nathan 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...
  5. pmc Phosphorylation controls a dual-function polybasic nuclear localization sequence in the adapter protein SH2B1β to regulate its cellular function and distribution
    Travis 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
    ....
  6. pmc 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 genes
    Travis 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
    ....
  7. pmc 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 3/10
    Linyi 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
    ....
  8. ncbi SH2B1 enhances leptin signaling by both Janus kinase 2 Tyr813 phosphorylation-dependent and -independent mechanisms
    Zhiqin 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...
  9. pmc Adapter protein SH2-Bbeta stimulates actin-based motility of Listeria monocytogenes in a vasodilator-stimulated phosphoprotein (VASP)-dependent fashion
    Maria Diakonova
    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
    Infect Immun 75:3581-93. 2007
    ....
  10. ncbi Recent advances in growth hormone signaling
    Nathan 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...
  11. ncbi Multiplexed detection of protein-peptide interaction and inhibition using capillary electrophoresis
    Peilin 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...
  12. ncbi SH2B1 (SH2-B) and JAK2: a multifunctional adaptor protein and kinase made for each other
    Travis 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...
  13. pmc Phosphorylation of the adaptor protein SH2B1β regulates its ability to enhance growth hormone-dependent macrophage motility
    Hsiao 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)...

Research Grants31

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  2. DEVELOPMENTAL BIOLOGY OF HUMAN ERYTHROPOIESIS
    Stuart H Orkin; Fiscal Year: 2013
    ..abstract_text> ..
  3. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  4. PATHOPHYSIOLOGY OF THE ENDOTHELIUM
    Francis W Luscinskas; Fiscal Year: 2013
    ..g., heart attacks and strokes), as well as other organs and tissues of the body. These mechanistic insights may help identify novel therapeutic targets for the treatment of a broad spectrum of inflammatory diseases. ..
  5. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  6. CSHL CANCER CENTER SUPPORT GRANT
    BRUCE W STILLMAN; Fiscal Year: 2013
    ....
  7. IBD and Mucosal Inflammation, Immunology, and Microbiology of the GI Tract
    Eugene B Chang; Fiscal Year: 2013
    ..Through its cost-effective, enabling technologies and services, the DDRCC has been a major factor in the advancement of scholarship and discovery in IBD and digestive diseases at the University of Chicago. ..
  8. TSH RECEPTOR MULTIMERIZATION
    TERRY FRANCIS DAVIES; Fiscal Year: 2013
    ....
  9. Mechanisms of Integrin-Mediated Costimulation in T Cells
    Stephen C Bunnell; Fiscal Year: 2013
    ..In this manner, we expect to gain useful insights into the underlying causes of common medical conditions, including asthma, multiple sclerosis, diabetes, inflammatory bowel disease, and atherosclerosis. ..
  10. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  11. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  12. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  13. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
    ..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
  14. Re-wiring of gene expression in the meiotic state
    ALLEN BRUCE FUTCHER; Fiscal Year: 2013
    ..Dr. Leatherwood) The research Projects will be supported by a Microarray Core Facility, which will play a crucial role in all four projects. ..
  15. Superfund Metal Mixtures, Biomarkers and Neurodevelopment
    David C Bellinger; Fiscal Year: 2013
    ..Aim 4- To promote rapid dissemination of significant research findings;and Aim 5- Compliance- To ensure compliance with NIH requirements for data and resource-sharing and the human and animal institutional review board requirements ..
  16. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  17. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  18. Mechanisms of how nuclear envelope bridges link nuclei to the cytoskeleton.
    Daniel A Starr; Fiscal Year: 2013
    ....
  19. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..