Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation

Grimley, Philip M.; Fan, Daiming; Rui, Hallgeir

doi:10.1016/s1359-6101(99)00011-8

Cited by 213 publications

(218 citation statements)

References 271 publications

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“…Phosphorylation of the Tyr-694 and Tyr-699 residues of Stat5a and Stat5b, respectively, leads to activation of the Stat5 proteins (Grimley et al, 1999). We first examined EGF receptor-mediated tyrosine phosphorylation of Stat5a and Stat5b in the hepatocytes, comparing the effects with the responses to PRL and GH.…”

Section: Effect Of Egf Tgfa Prl and Gh On Tyrosine Phosphorylationmentioning

confidence: 99%

“…Ser-730 on Stat5b can be phosphorylated (Grimley et al, 1999). The functional importance of this is not clear but there is evidence that phosphorylation of Ser-730 modulates the effects on gene transcription of Stat5b (Park et al, 2001).…”

Section: Constitutive Serine Phosphorylation Of Stat5bmentioning

confidence: 99%

“…In contrast, Stat3 may have promitogenic and antiapoptotic effects and has been implicated in malignant transformation in some cells (Bromberg et al, 1999;Song and Rubin Grandis, 2000). Stat5a and Stat5b in hematopoietic cells seem to promote growth, inhibit apoptosis, and may be involved in malignant transformation (Matsumura et al, 1999;Nosaka et al, 1999;Demoulin et al, 2000), and are also essential mediators of the effects of prolactin (PRL) and growth hormone (GH) as well as IL-2 and other cytokines (Groner and Gouilleux, 1995;Grimley et al, 1999;Moriggl et al, 1999;Herrington et al, 2000;Lin and Leonard, 2000). However, although STAT proteins in some cells have been found to be phosphorylated and activated in response to growth factors, including EGF (Ruff-Jamison et al, 1993Richer et al, 1998;Guren et al, 1999;Luetteke et al, 1999;Olayioye et al, 1999), PDGF (Valgeirsdottir et al, 1998;Sachsenmaier et al, 1999), and VEGF (Bartoli et al, 2000), their exact function in receptor tyrosine kinase signaling has not been defined, and the role of STAT proteins in EGF receptor-mediated mitogenic mechanisms is not known.…”

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confidence: 99%

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EGF receptor‐mediated, c‐Src‐dependent, activation of Stat5b is downregulated in mitogenically responsive hepatocytes

Guren

Ødegård

Abrahamsen

et al. 2003

Journal Cellular Physiology

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Signal transducer and activator of transcription (STAT) proteins may be activated by epidermal growth factor (EGF), but their role in EGF receptor-mediated mitogenic signaling is not clear. We previously showed that Stat5b was activated by EGF in rat hepatocytes in primary monolayer culture. In the present study, we found that EGF induced tyrosine phosphorylation of Stat5b both on Tyr-699, which correlated with specific DNA binding activity, and also on other tyrosine residues. The Src tyrosine kinase inhibitor CGP77675 blocked the EGF-induced activation of Stat5b, but did not affect the Stat5b activation by growth hormone (GH) or prolactin (PRL). The Stat5b response to EGF was most pronounced soon (3 h) after plating (early G 1 ) and at high cell density (50,000 hepatocytes per cm 2 ). However, at this cell density EGF did not stimulate DNA synthesis. In hepatocytes at 24 h of culturing (mid/late G 1 ) with 20,000 cells per cm 2 , EGF induced strong phosphorylation of the EGF receptor, as well as Shc and ERK, and stimulated DNA synthesis, but did not activate Stat5b, although the Stat5b response to GH or PRL was retained. A strong GHinduced Stat5b activation neither influenced the DNA synthesis alone nor enhanced the mitogenic effect of EGF. The results show that EGF induces tyrosine phosphorylation and DNA-binding activity of Stat5b in a manner different from GH and PRL, apparently by a Src-dependent mechanism. The data also provide further evidence that Stat5b is not required for mitogenic signaling from the EGF receptor.

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Section: Effect Of Egf Tgfa Prl and Gh On Tyrosine Phosphorylationmentioning

confidence: 99%

Section: Constitutive Serine Phosphorylation Of Stat5bmentioning

confidence: 99%

mentioning

confidence: 99%

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EGF receptor‐mediated, c‐Src‐dependent, activation of Stat5b is downregulated in mitogenically responsive hepatocytes

Guren

Ødegård

Abrahamsen

et al. 2003

Journal Cellular Physiology

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“…Here, we have investigated the effect of Rho GTPases on the regulation of Stat5. Two separately encoded Stat5 transcription factors, Stat5a and Stat5b, coexist (Grimley et al, 1999). Although Stat5 was initially discovered as a prolactin-stimulated ovine mammary gland factor (Gouilleux et al, 1994), it has become evident that a large number of different cytokines, growth factors, and oncogenes promote tyrosine phosphorylation and transcriptional activation of Stat5a and Stat5b (Grimley et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Two separately encoded Stat5 transcription factors, Stat5a and Stat5b, coexist (Grimley et al, 1999). Although Stat5 was initially discovered as a prolactin-stimulated ovine mammary gland factor (Gouilleux et al, 1994), it has become evident that a large number of different cytokines, growth factors, and oncogenes promote tyrosine phosphorylation and transcriptional activation of Stat5a and Stat5b (Grimley et al, 1999). Activation of Stat5 follows a paradigm common to all Stat proteins, in which phosphorylation of a single C-terminal tyrosine residue promotes Stat oligomerization via their SH2 domains, nuclear migration, and DNA binding to specific elements.…”

Section: Introductionmentioning

confidence: 99%

STAT5a Activation Mediates the Epithelial to Mesenchymal Transition Induced by Oncogenic RhoA.

Benitah¹,

Valerón²,

Rui

et al. 2003

MBoC

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The involvement of Rho GTPases in signal transduction pathways leading to transcription activation is one of the major roles of this family of GTPases. Thus, the identification of transcription factors regulated by Rho GTPases and the understanding of the mechanisms of their activation and its biological outcome are of great interest. Here, we provide evidence that Rho GTPases modulate Stat5a, a transcription factor of the family of signal transducers and activators of transcription. RhoA triggers tyrosine phosphorylation (Y696) of Stat5a via a JAK2-dependent mechanism and promotes DNA-binding activity of Stat5a. Tyrosine phosphorylation of Stat5a is also stimulated physiologically by lysophosphatidic acid (LPA) in a Rho-dependent manner. Simultaneously, RhoA reduces serine phosphorylation of Stat5a at both serine residues S726 and S780, resulting in a further increase of activity as defined by mutagenesis experiments. Furthermore, serine dephosphorylation of Stat5a by RhoA does not take place by down-modulation of either JNK1, MEK1, or p38 MAP kinases, as determined by transfection experiments or chemical inhibition of both MEK1, p38, and JNK serine kinases. Thus, RhoA regulates Stat5a via tyrosine phosphorylation and via a yet to be determined novel down-modulating pathway that involves serine dephosphorylation. Finally, we provide evidence for a role of Stat5a in RhoA-induced epithelial-to-mesenchymal transition with concomitant increase in vimentin expression, E-cadherin down-regulation, and cell motility

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Age‐associated myeloid malignancies – the role of STAT3 and STAT5 in myelodysplastic syndrome and acute myeloid leukemia

Fasouli,

Katsantoni

2024

FEBS Letters

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In the last few decades, the increasing human life expectancy has led to the inflation of the elderly population and consequently the escalation of age‐related disorders. Biological aging has been associated with the accumulation of somatic mutations in the Hematopoietic Stem Cell (HSC) compartment, providing a fitness advantage to the HSCs leading to clonal hematopoiesis, that includes non‐malignant and malignant conditions (i.e. Clonal Hematopoiesis of Indeterminate Potential, Myelodysplastic Syndrome and Acute Myeloid Leukemia). The Janus Kinase‐Signal Transducer and Activator of Transcription (JAK–STAT) pathway is a key player in both normal and malignant hematopoiesis. STATs, particularly STAT3 and STAT5, are greatly implicated in normal hematopoiesis, immunity, inflammation, leukemia, and aging. Here, the pleiotropic functions of JAK–STAT pathway in age‐associated hematopoietic defects and of STAT3 and STAT5 in normal hematopoiesis, leukemia, and inflammaging are reviewed. Even though great progress has been made in deciphering the role of STATs, further research is required to provide a deeper understanding of the molecular mechanisms of leukemogenesis, as well as novel biomarkers and therapeutic targets for improved management of age‐related disorders.

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Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation

Cited by 213 publications

References 271 publications

EGF receptor‐mediated, c‐Src‐dependent, activation of Stat5b is downregulated in mitogenically responsive hepatocytes

EGF receptor‐mediated, c‐Src‐dependent, activation of Stat5b is downregulated in mitogenically responsive hepatocytes

STAT5a Activation Mediates the Epithelial to Mesenchymal Transition Induced by Oncogenic RhoA.

Age‐associated myeloid malignancies – the role of STAT3 and STAT5 in myelodysplastic syndrome and acute myeloid leukemia

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