PMID- 10218944
OWN - NLM
STAT- MEDLINE
DCOM- 19990506
LR  - 20161124
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 140
IP  - 5
DP  - 1999 May
TI  - Insulin receptor substrate-1 enhances growth hormone-induced proliferation.
PG  - 1972-83
AB  - GH exerts a variety of metabolic and growth-promoting effects. GH induces
      activation of the GH receptor (GHR)-associated cytoplasmic tyrosine kinase, JAK2,
      resulting in tyrosine phosphorylation of the GHR and activation of STAT (signal
      transducer and activator of transcription), Ras-mitogen-activated protein kinase,
      and phosphoinositol 3-kinase signaling pathways, among others. GH-stimulated
      tyrosine phosphorylation of insulin receptor substrate (IRS) proteins has been
      demonstrated in vitro and in vivo. IRS-1 is a multiply phosphorylated cytoplasmic
      docking protein involved in metabolic and proliferative signaling by insulin,
      IL-4, and other cytokines, but the physiological role of IRS-1 in GH signaling is
      unknown. In this study, as noted by others, we detected in murine 3T3-F442A
      pre-adipocytes GH-dependent tyrosine phosphorylation of IRS-1 and specific
      GH-induced coimmunoprecipitation with JAK2 of a tyrosine phosphoprotein
      consistent with IRS-1. We further examined this interaction by in vitro affinity 
      precipitation experiments with glutathione-S-transferase fusion proteins
      incorporating regions of rat IRS-1 and, as a source of JAK2, extracts of
      3T3-F442A cells. Fusion proteins containing amino-terminal regions of IRS-1 that 
      include the pleckstrin homology, phosphotyrosine-binding, and Shc and IRS-1
      NPXY-binding domains, but not those containing other IRS-1 regions or
      glutathione-S-transferase alone, bound JAK2 from cell extracts.
      Tyrosine-phosphorylated JAK2 resulting from GH stimulation was included in the
      amino-terminal IRS-1 fusion precipitates; however, neither tyrosine
      phosphorylation of JAK2 nor treatment of cells with GH before extraction was
      necessary for the specific JAK2-IRS-1 interaction to be detected. In contrast, in
      this assay, specific insulin receptor association with the IRS-1
      phosphotyrosine-binding, and Shc and IRS-1 NPXY-binding domains was insulin and
      phosphotyrosine dependent, as previously shown. To test for significance of IRS-1
      with regard to GH signaling, IRS- and GHR-deficient 32D cells were stably
      reconstituted with the rabbit (r) GHR, either alone (32D-rGHR) or with IRS-1
      (32D-rGHR-IRS-1). As assayed by three independent methods, GH induced
      proliferation in 32D-rGHR cells, even in the absence of transfected IRS-1.
      Notably, however, GH-induced proliferation was markedly enhanced in cells
      expressing IRS-1. Similarly, GH-induced mitogen-activated protein kinase
      activation was significantly augmented in IRS-1-expressing cells relative to that
      in cells harboring no IRS-1. These results indicate that IRS-1 enhances
      GH-induced proliferative signaling.
FAU - Liang, L
AU  - Liang L
AD  - Department of Medicine, University of Alabama, Birmingham 35294, USA.
FAU - Zhou, T
AU  - Zhou T
FAU - Jiang, J
AU  - Jiang J
FAU - Pierce, J H
AU  - Pierce JH
FAU - Gustafson, T A
AU  - Gustafson TA
FAU - Frank, S J
AU  - Frank SJ
LA  - eng
GR  - DK46395/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (IRS1 protein, human)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Irs1 protein, mouse)
RN  - 0 (Irs1 protein, rat)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptors, Somatotropin)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (SHC1 protein, human)
RN  - 0 (Shc Signaling Adaptor Proteins)
RN  - 0 (Shc1 protein, mouse)
RN  - 0 (Shc1 protein, rat)
RN  - 0 (Src Homology 2 Domain-Containing, Transforming Protein 1)
RN  - 12629-01-5 (Human Growth Hormone)
RN  - 21820-51-9 (Phosphotyrosine)
RN  - EC 2.5.1.18 (Glutathione Transferase)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Jak2 protein, mouse)
RN  - EC 2.7.10.2 (Jak2 protein, rat)
RN  - EC 2.7.10.2 (Janus Kinase 2)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
SB  - AIM
SB  - IM
MH  - 3T3 Cells
MH  - *Adaptor Proteins, Signal Transducing
MH  - *Adaptor Proteins, Vesicular Transport
MH  - Animals
MH  - Binding Sites
MH  - COS Cells
MH  - Calcium-Calmodulin-Dependent Protein Kinases/metabolism
MH  - Cell Division/*drug effects
MH  - Glutathione Transferase/genetics
MH  - Human Growth Hormone/*pharmacology
MH  - Humans
MH  - Immunosorbent Techniques
MH  - Insulin Receptor Substrate Proteins
MH  - Janus Kinase 2
MH  - Mice
MH  - Phosphoproteins/genetics/metabolism/*pharmacology
MH  - Phosphorylation
MH  - Phosphotyrosine/metabolism
MH  - Protein-Tyrosine Kinases/metabolism
MH  - Proteins/metabolism
MH  - *Proto-Oncogene Proteins
MH  - Rabbits
MH  - Rats
MH  - Receptor, Insulin/metabolism
MH  - Receptors, Somatotropin/genetics/metabolism
MH  - Recombinant Fusion Proteins/metabolism
MH  - Shc Signaling Adaptor Proteins
MH  - Signal Transduction
MH  - Src Homology 2 Domain-Containing, Transforming Protein 1
EDAT- 1999/04/28 00:00
MHDA- 1999/04/28 00:01
CRDT- 1999/04/28 00:00
PHST- 1999/04/28 00:00 [pubmed]
PHST- 1999/04/28 00:01 [medline]
PHST- 1999/04/28 00:00 [entrez]
AID - 10.1210/endo.140.5.6724 [doi]
PST - ppublish
SO  - Endocrinology. 1999 May;140(5):1972-83. doi: 10.1210/endo.140.5.6724.