title: The role of receptor dimerization domain residues in growth hormone signaling.
abstract: While there is a considerable amount of evidence that signal transduction by the growth hormone (GH) receptor requires receptor homodimerization, there has been no systematic study of the role of receptor dimerization domain residues in this process. In conjunction with the distances derived from the crystal structure of the hGH-hGH receptor (extracellular domain) complex, we have used a luciferase-based c-fos promoter reporter assay in transiently transfected Chinese hamster ovary (CHO) cells, and stable receptor expressing CHO cell populations to define the dimerization domain residues needed for effective signaling. In addition to alanine substitution, we have used both aspartate and lysine substitutions to allow us to provide evidence for proximity relations through charge complementation. Introduced cysteine substitutions were also used, but unlike the erythropoietin receptor, these were unable to generate constitutively active receptor. We conclude that serine 145, histidine 150, aspartate 152, tyrosine 200, and serine 201, but not leucine 146 or threonine 147 are required for effective signal transduction through the dimerization domain. This information may be valuable in designing small molecule antagonists of GH and other cytokines that block dimerization by binding to the dimerization domain.
authors.affiliation: Physiology & Pharmacology Department and Centre for Molecular & Cellular Biology, University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Brinkworth
authors.forename: M J
authors.initials: MJ
authors.lastname: Waters
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D019281:Dimerization; D013006:Growth Hormone / Q000378:metabolism*; D009154:Mutation; D011817:Rabbits; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011986:Receptors, Somatotropin; D013006:Growth Hormone