The membrane proximal region of the cytoplasmic domain of the growth hormone receptor is involved in the activation of Stat 3

Sotiropoulos, Athanassia; Moutoussamy, Soraya; Binart, Nadine; Kelly, Paul A.; Finidori, J.

doi:10.1016/0014-5793(95)00734-q

Cited by 42 publications

(21 citation statements)

References 34 publications

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“…Second, the JAKs could directly phosphorylate Stat3 itself, an activity presumably not enabled in PDGFR. Third, JAKs could provide Stat3 recruitment sites in the receptor complex, as proposed for Jak2 in response to growth hormone receptor activation (19).…”

Section: Discussionmentioning

confidence: 99%

Distinct Mechanisms of Activation of Stat1 and Stat3 by Platelet-Derived Growth Factor Receptor in a Cell-Free System

Vignais

Gilman

1999

Molecular and Cellular Biology

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Ligand-dependent activation of the platelet-derived growth factor receptor (PDGFR) in fibroblasts in culture leads to the activation of the JAK family of protein-tyrosine kinases and of the transcription factors Stat1 and Stat3. To determine the biochemical mechanism of STAT activation by PDGFR, we devised a cell-free system composed of a membrane fraction from cells overexpressing PDGFR. When supplemented with crude cytosol, the membrane fraction supported PDGF-and ATP-dependent activation of both Stat1 and Stat3. However, the extent of Stat3 activation differed depending on the source of the cytosolic fraction. Using purified recombinant STAT proteins produced in Escherichia coli, we found that Stat1 could be activated by immunopurified PDGFR and showed no additional requirement for membrane-or cytosol-derived proteins. In contrast, activation of Stat3 exhibited a strong requirement for the cytosolic fraction. The activity present in the cytosolic fraction could be depleted with antibodies to JAK proteins. We conclude that the mechanisms of activation of Stat1 and Stat3 by PDGFR are distinct. Stat1 activation appears to result from a direct interaction with the receptor, whereas Stat3 activation additionally requires JAK proteins.Proteins of the STAT family of transcription factors are activated by a wealth of cytokines and polypeptide growth factors. Activation by cytokine receptors requires members of the JAK family of protein tyrosine kinases (2-4, 8-10, 15, 17, 24). The general model for STAT activation was based on the paradigm of STAT activation by the interferon receptors (5, 18). Gamma interferon activates both Jak1 and Jak2, which are in turn required for the activation of Stat1 (12,25). Alpha interferon activates Jak1 and Tyk2, leading to the activation of Stat1 and Stat2 (12,21). For interferons and other cytokines that act through cell-surface receptors that lack intrinsic protein-tyrosine kinase activity, receptor-associated JAKs provide the catalytic activity responsible for receptor phosphorylation to create docking sites for signaling proteins such as STATs and presumably for phosphorylation of the proteins recruited to the phosphorylated receptor.Polypeptide growth factors, such as epidermal growth factor and platelet-derived growth factor (PDGF), also activate JAKs and STATs (11,22). Because the receptors for these factors harbor intrinsic protein-tyrosine kinase activity, the role of receptor-activated JAKs, if any, in STAT activation by these receptors remains unclear. We used a cell-free system and partially purified proteins to examine the biochemical steps in STAT activation by the PDGF receptor (PDGFR). We found that the mechanisms of activation of Stat1 and Stat3 are different and that JAKs may be required only for the activation of Stat3. MATERIALS AND METHODSCell cultures and cellular extracts. The cell line 2fTGH.PS1 (22), derived from the human fibrosarcoma HT1080 cells, was grown in Dulbecco modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS).Cytosolic ext...

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Section: Discussionmentioning

confidence: 99%

Distinct Mechanisms of Activation of Stat1 and Stat3 by Platelet-Derived Growth Factor Receptor in a Cell-Free System

Vignais

Gilman

1999

Molecular and Cellular Biology

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“…Dual Luciferase Assays-Functional STAT5 activation was assessed by measuring luciferase production of Bosc cells transfected with the pLHRE-Luc (lactogenic hormone responsive element), which contains six copies of the prolactin STAT5 binding site in the rat ␤-casein promoter (19). As an internal control the pRL-TK vector (Promega, Madison, WI) was used.…”

Section: Methodsmentioning

confidence: 99%

Structural Requirements of the Extracellular to Transmembrane Domain Junction for Erythropoietin Receptor Function

Kubatzky

Liu

Goldgraben

et al. 2005

Journal of Biological Chemistry

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“…However, signi®cantly truncated forms of GH receptor which lack most or all phosphorylated tyrosines can mediate GH-induced tyrosyl phosphorylation of STATs 1 and 3 and binding of STATs 1 and 3 to the Sis inducible element (SIE) of c-fos. This suggests that speci®c phosphorylated tyrosines in GH receptor may not be essential for activation of STATs 1 and 3 by GH (Smit et al, 1996;Sotiropoulos et al, 1995Sotiropoulos et al, , 1996Yi et al, 1996). While not essential for GHdependent activation of STATs 1 and 3, phosphorylated tyrosine(s) in the N-terminal half of the cytoplasmic domain of the rat GH receptor may contribute to maximal activation of STATs 1 and 3 in response to GH (Smit et al, 1996).…”

Section: Mechanism Of Activation Of Stat Proteins By Ghmentioning

confidence: 99%

The role of STAT proteins in growth hormone signaling

et al. 2000

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Growth hormone (GH) has long been known to be the body's primary regulator of body growth and a regulator of metabolism, yet the mechanisms by which GH regulates the transcription of speci®c genes required for these processes are just now being delineated. GH binding to its receptor recruits and activates the receptor-associated JAK2 that in turn phosphorylates tyrosines within itself and the GH receptor. These tyrosines form binding sites for a number of signaling proteins, including members of the family of signal transducers and activators of transcription (STAT). Among the known signaling molecules for GH, STAT proteins play a particularly prominent role in the regulation of gene transcription. This paper will review what is currently understood about which STAT proteins are regulated by GH, how they are regulated by GH, the GH-dependent genes they regulate, and discuss current theories about how GH-activated STAT signaling is regulated. Particular attention will be given to the novel role that STAT5 plays in sexually dimorphic gene expression in the liver as determined by the secretory pattern of GH and the role of STAT5 in body growth.

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The membrane proximal region of the cytoplasmic domain of the growth hormone receptor is involved in the activation of Stat 3

Cited by 42 publications

References 34 publications

Distinct Mechanisms of Activation of Stat1 and Stat3 by Platelet-Derived Growth Factor Receptor in a Cell-Free System

Distinct Mechanisms of Activation of Stat1 and Stat3 by Platelet-Derived Growth Factor Receptor in a Cell-Free System

Structural Requirements of the Extracellular to Transmembrane Domain Junction for Erythropoietin Receptor Function

The role of STAT proteins in growth hormone signaling

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