title: Growth hormone signaling pathways.
abstract: Over 20years ago, our laboratory showed that growth hormone (GH) signals through the GH receptor-associated tyrosine kinase JAK2. We showed that GH binding to its membrane-bound receptor enhances binding of JAK2 to the GHR, activates JAK2, and stimulates tyrosyl phosphorylation of both JAK2 and GHR. The activated JAK2/GHR complex recruits a variety of signaling proteins, thereby initiating multiple signaling pathways and cellular responses. These proteins and pathways include: 1) Stat transcription factors implicated in the expression of multiple genes, including the gene encoding insulin-like growth factor 1; 2) Shc adapter proteins that lead to activation of the grb2-SOS-Ras-Raf-MEK-ERK1,2 pathway; 3) insulin receptor substrate proteins implicated in the phosphatidylinositol-3-kinase and Akt pathway; 4) signal regulatory protein α, a transmembrane scaffold protein that recruits proteins including the tyrosine phosphatase SHP2; and 5) SH2B1, a scaffold protein that can activate JAK2 and enhance GH regulation of the actin cytoskeleton. Our recent work has focused on the function of SH2B1. We have shown that SH2B1β is recruited to and phosphorylated by JAK2 in response to GH. SH2B1 localizes to the plasma membrane, cytoplasm and focal adhesions; it also cycles through the nucleus. SH2B1 regulates the actin cytoskeleton and promotes GH-dependent motility of RAW264.7 macrophages. Mutations in SH2B1 have been found in humans exhibiting severe early-onset childhood obesity and insulin resistance. These mutations impair SH2B1 enhancement of GH-induced macrophage motility. As SH2B1 is expressed ubiquitously and is also recruited to a variety of receptor tyrosine kinases, our results raise the possibility that effects of SH2B1 on the actin cytoskeleton in various cell types, including neurons, may play a role in regulating body weight.
authors.affiliation: Departments of Molecular and Integrative Physiology and of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109, United States. Electronic address: cartersu@umich.edu.
authors.forename: Christin
authors.initials: C
authors.lastname: Carter-Su
authors.affiliation: Departments of Molecular and Integrative Physiology and of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Schwartz
authors.affiliation: Departments of Molecular and Integrative Physiology and of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109, United States.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Argetsinger
mesh_terms: D008841:Actin Cytoskeleton; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D053614:Janus Kinase 2 / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D063766:Pediatric Obesity / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D011986:Receptors, Somatotropin; C518910:SH2B1 protein, human; D050791:STAT Transcription Factors; D013006:Growth Hormone; D019869:Phosphatidylinositol 3-Kinases; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Growth hormone; JAK2; SH2B1; Signal transduction