title: SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone.
abstract: Growth hormone (GH) has long been known to be a primary determinant of body height and an important regulator of body metabolism, yet the cellular and molecular bases for these effects of GH are only beginning to be understood. In 1993, GH receptor (GHR) was first observed to bind to the tyrosine kinase JAK2. GH increased JAK2's affinity for GHR, potently activated JAK2, and stimulated the phosphorylation of tyrosines within JAK2 and the cytoplasmic domain of GHR. In the intervening six years, a variety of signaling molecules have been identified that are tyrosyl phosphorylated in response to GH, presumably by the activated JAK2. These signaling molecules include 1) the latent cytoplasmic transcription factors--designated signal transducers and activators of transcription (Stats)--that have been implicated in the regulation of a variety of GH-dependent genes; 2) Shc proteins that lead to activation of the Ras-MAP kinase pathway: and 3) insulin receptor substrate (IRS) proteins that bind and thereby activate phosphatidylinositol 3' kinase and presumably other proteins. Recently, we have identified two additional signaling molecules for GH that bind to JAK2 and are phosphorylated on tyrosines in response to GH: SH2-B and signal regulated protein (SIRP). Based upon amino acid sequence analysis, SH2-B is presumed to be a cytoplasmic adapter protein. It binds with high affinity via its SH2 domain to phosphorylated tyrosines within JAK2. GH-induced binding of SH2-B to JAK2 via this site potently activates JAK2, leading to enhanced tyrosyl phosphorylation of Stat proteins and other cellular proteins. Because of its other potential protein-protein interaction domains and its recruitment and phosphorylation by kinases that are not activated by SH2-B, SH2-B is thought likely to mediate other, more-specific actions of GH, as yet to be determined. SIRP is a transmembrane protein that is now known to bind to integrin-associated protein. It appears to bind directly to JAK2 by a process that does not require tyrosyl phosphorylation, although is itself highly phosphorylated on tyrosines in response to GH. The phosphorylated SIRP recruits one or more molecules of the tyrosine phosphatase SHP2 that, in turn, de-phosphorylates SIRP and most likely JAK2. Thus, SIRP is predicted to be a negative regulator of GH action. It seems likely that the diverse actions of GH will be found to require coordinated interaction of all of these signaling proteins with each other as well as with other signaling molecules that are activated by GH and the numerous other ligands that are present at cells during a response to GH.
authors.affiliation: Department of Physiology, The University of Michigan Medical School, Ann Arbor 48109-0622, USA.
authors.forename: C
authors.initials: C
authors.lastname: Carter-Su
authors.forename: L
authors.initials: L
authors.lastname: Rui
authors.forename: M R
authors.initials: MR
authors.lastname: Stofega
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D011518:Proto-Oncogene Proteins; C518910:SH2B1 protein, human; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins