Activated STAT5 proteins induce activation of the PI 3-kinase/Akt and Ras/MAPK pathways via the Gab2 scaffolding adapter

The active forms of STAT5A (signal transducer and activator of transcription 5A) and STAT5B are able to relieve the cytokine dependence of haematopoietic cells and to induce leukaemia in mice. We have demonstrated previously that activation of the PI3K (phosphoinositide 3-kinase) signalling cascade plays a major role in cell growth and survival induced by these proteins. Interaction between STAT5 and p85, the regulatory subunit of the PI3K, has been suggested to be required for this activation. We show in the present study that the scaffolding protein Gab2 [Grb2 (growth-factor-receptor-bound protein 2)-associated binder-2] is an essential component of this interaction. Gab2 is persistently tyrosine-phosphorylated in Ba/F3 cells expressing caSTAT5 (constitutively activated STAT5), independent of JAK2 (Janus kinase 2) activation where it interacts with STAT5, p85 and Grb2, but not with Shp2 [SH2 (Src homology 2)-domain-containing tyrosine phosphatase] proteins. Interaction of STAT5 with Gab2 was also observed in Ba/F3 cells stimulated with interleukin-3 or expressing the oncogenic fusion protein Tel–JAK2. The MAPKs (mitogen-activated protein kinases) ERK1 (extracellular-signal-regulated kinase 1) and ERK2 were constitutively activated in the caSTAT5-expressing cells and were found to be required for caSTAT5-induced cell proliferation. Overexpression of Gab2-3YF, a mutant of Gab2 incapable of binding PI3K, inhibited the proliferation and survival of caSTAT5-expressing cells as well as ERK1/2 and Akt/protein kinase B phosphorylation. Taken together, our results indicate that Gab2 is required for caSTAT5-induced cell proliferation by regulating both the PI3K/Akt and the Ras/MAPK pathways.

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The tyrosine phosphatase CD148 interacts with the p85 regulatory subunit of phosphoinositide 3-kinase

Biochemical Journal ◽

10.1042/bj20071317 ◽

2008 ◽

Vol 413 (1) ◽

pp. 193-200 ◽

Cited By ~ 33

Author(s):

Nobuo Tsuboi ◽

Tadahiko Utsunomiya ◽

Richard L. Roberts ◽

Hideyuki Ito ◽

Keiko Takahashi ◽

...

Keyword(s):

Tyrosine Phosphatase ◽

Growth Factor Receptor ◽

Regulatory Subunit ◽

Mutant Form ◽

Dependent Manner ◽

Screening Assay ◽

Intact Cells ◽

Pi3k Activity ◽

Phosphoinositide 3 Kinase

CD148 is a transmembrane tyrosine phosphatase that has been implicated in the regulation of cell growth and transformation. However, the signalling mechanisms of CD148 are incompletely understood. To identify the specific intracellular molecules involved in CD148 signalling, we carried out a modified yeast two-hybrid screening assay. Using the substrate-trapping mutant form of CD148 (CD148 D/A) as bait, we recovered the p85 regulatory subunit of PI3K (phosphoinositide 3-kinase). CD148 D/A, but not catalytically active CD148, interacted with p85 in a phosphorylation-dependent manner in vitro and in intact cells. Growth factor receptor and PI3K activity were also trapped by CD148 D/A via p85 from pervanadate-treated cell lysates. CD148 prominently and specifically dephosphorylated p85 in vitro. Co-expression of CD148 reduced p85 phosphorylation induced by active Src, and attenuated the increases in PI3K activity, yet CD148 did not alter the basal PI3K activity. Finally, CD148 knock-down by siRNA (short interfering RNA) increased PI3K activity on serum stimulation. Taken together, these results demonstrate that CD148 may interact with and dephosphorylate p85 when it is phosphorylated and modulate the magnitude of PI3K activity.

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Bovine type I collagen inhibits Raw264.7 cell proliferation through phosphoinositide 3-kinase- and mitogen-activated protein kinase-dependent down-regulation of cyclins D1, A and B1

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ◽

10.1016/j.bbamcr.2004.11.004 ◽

2005 ◽

Vol 1744 (1) ◽

pp. 47-57 ◽

Cited By ~ 11

Author(s):

Min Kyung Cho ◽

Seung Hoon Suh ◽

Chang Ho Lee ◽

Sang Geon Kim

Keyword(s):

Cell Proliferation ◽

Protein Kinase ◽

Type I Collagen ◽

Mitogen Activated Protein Kinase ◽

Type I ◽

Down Regulation ◽

Mitogen Activated Protein ◽

Raw264.7 Cell ◽

Phosphoinositide 3 Kinase ◽

Bovine Type

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Regulation of EphB2 activation and cell repulsion by feedback control of the MAPK pathway

The Journal of Cell Biology ◽

10.1083/jcb.200807151 ◽

2008 ◽

Vol 183 (5) ◽

pp. 933-947 ◽

Cited By ~ 51

Author(s):

Alexei Poliakov ◽

Maria L. Cotrina ◽

Andrea Pasini ◽

David G. Wilkinson

Keyword(s):

Feedback Loop ◽

Fibroblast Growth Factor Receptor ◽

Mapk Pathway ◽

Tyrosine Phosphatase ◽

Growth Factor Receptor ◽

Mitogen Activated Protein Kinase ◽

Eph Receptor ◽

Mitogen Activated Protein ◽

Mediate Cell ◽

Cell Repulsion

In this study, we investigated whether the ability of Eph receptor signaling to mediate cell repulsion is antagonized by fibroblast growth factor receptor (FGFR) activation that can promote cell invasion. We find that activation of FGFR1 in EphB2-expressing cells prevents segregation, repulsion, and collapse responses to ephrinB1 ligand. FGFR1 activation leads to increased phosphorylation of unstimulated EphB2, which we show is caused by down-regulation of the leukocyte common antigen–related tyrosine phosphatase receptor that dephosphorylates EphB2. In addition, FGFR1 signaling inhibits further phosphorylation of EphB2 upon stimulation with ephrinB1, and we show that this involves a requirement for the mitogen-activated protein kinase (MAPK) pathway. In the absence of activated FGFR1, EphB2 activates the MAPK pathway, which in turn promotes EphB2 activation in a positive feedback loop. However, after FGFR1 activation, the induction of Sprouty genes inhibits the MAPK pathway downstream of EphB2 and decreases cell repulsion and segregation. These findings reveal a novel feedback loop that promotes EphB2 activation and cell repulsion that is blocked by transcriptional targets of FGFR1.

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The Q43L mutant of neuregulin 2β is a pan-ErbB receptor antagonist

Biochemical Journal ◽

10.1042/bj20110921 ◽

2012 ◽

Vol 443 (1) ◽

pp. 133-144 ◽

Cited By ~ 2

Author(s):

Kristy J. Wilson ◽

Christopher P. Mill ◽

Richard M. Gallo ◽

Elizabeth M. Cameron ◽

Henry VanBrocklin ◽

...

Keyword(s):

Cell Proliferation ◽

Tyrosine Phosphorylation ◽

Kinase Activity ◽

Growth Factor Receptor ◽

Erbb Receptor ◽

Pharmacological Agents ◽

Akt Phosphorylation ◽

Agonist Stimulation ◽

Phosphoinositide 3 Kinase ◽

Stimulation Of

The ErbB4 receptor tyrosine kinase possesses both tumour suppressor and oncogenic activities. Thus pharmacological agents are needed to help elucidate ErbB4 functions. However, limitations of existing ErbB4 agonists and antagonists have led us to seek novel ErbB4 antagonists. The Q43L mutant of the ErbB4 agonist NRG2β (neuregulin 2β) stimulates ErbB4 tyrosine phosphorylation, yet fails to stimulate ErbB4 coupling to cell proliferation. Thus in the present paper we hypothesize that NRG2β/Q43L may be an ErbB4 antagonist. NRG2β/Q43L competitively antagonizes agonist stimulation of ErbB4 coupling to cell proliferation. NRG2β/Q43L stimulates less ErbB4 tyrosine phosphorylation than does NRG2β. In addition, NRG2β stimulation of cell proliferation requires PI3K (phosphoinositide 3-kinase) activity and NRG2β stimulates greater Akt phosphorylation than does NRG2β/Q43L. Moreover, EGFR [EGF (epidermal growth factor) receptor] kinase activity (but not that of ErbB4) is critical for coupling ErbB4 to proliferation. Experiments utilizing ErbB4 splicing isoforms and mutants suggest that NRG2β and NRG2β/Q43L may differentially stimulate ErbB4 coupling to the transcriptional co-regulator YAP (Yes-associated protein). Finally, NRG2β/Q43L competitively antagonizes agonist stimulation of EGFR and ErbB2/ErbB3, indicating that NRG2β/Q43L is a pan-ErbB antagonist. Thus we postulate that NRG2β/Q43L and other antagonistic ligands stimulate ErbB tyrosine phosphorylation on a set of residues distinct from that stimulated by agonists, thus suggesting a novel mechanism of ErbB receptor regulation. Moreover, NRG2β/Q43L and related ligand-based antagonists establish a paradigm for the discovery of anti-ErbB therapeutics.

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TNF-alpha employs a protein-tyrosine phosphatase to inhibit activation of hepatocyte growth factor receptor and hepatocyte growth factor-induced endothelial cell proliferation

Molecular and Cellular Biochemistry ◽

10.1007/s11010-008-9946-7 ◽

2008 ◽

Vol 322 (1-2) ◽

pp. 113-117 ◽

Cited By ~ 8

Author(s):

Masahiro Sugano ◽

Yoshiko Iwasaki ◽

Masako Abe ◽

Toyoki Maeda ◽

Keiko Tsuchida ◽

...

Keyword(s):

Cell Proliferation ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Growth Factor Receptor ◽

Endothelial Cell Proliferation ◽

Tnf Alpha ◽

Hepatocyte Growth Factor Receptor ◽

Hepatocyte Growth

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New Strategies in Colorectal Cancer: Biomarkers of Response to Epidermal Growth Factor Receptor Monoclonal Antibodies and Potential Therapeutic Targets in Phosphoinositide 3-Kinase and Mitogen-Activated Protein Kinase Pathways

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-09-2283 ◽

2010 ◽

Vol 16 (15) ◽

pp. 3811-3818 ◽

Cited By ~ 32

Author(s):

Arvind Dasari ◽

Wells A. Messersmith

Keyword(s):

Colorectal Cancer ◽

Epidermal Growth Factor Receptor ◽

Monoclonal Antibodies ◽

Growth Factor Receptor ◽

Cancer Biomarkers ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Epidermal Growth ◽

Phosphoinositide 3 Kinase ◽

New Strategies

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Discovery of novel non-peptide thrombopoietin mimetic compounds that induce megakaryocytopoiesis

Bioscience Reports ◽

10.1042/bsr20080086 ◽

2008 ◽

Vol 28 (5) ◽

pp. 275-285 ◽

Cited By ~ 6

Author(s):

Noriko Yamane ◽

Koji Takahashi ◽

Yoshikazu Tanaka ◽

Kazue Kato ◽

Masami Takayama ◽

...

Keyword(s):

Cell Line ◽

Bone Marrow Cells ◽

Tyrosine Phosphatase ◽

Growth Factor Receptor ◽

Janus Kinase ◽

Parent Cell ◽

Tyrosine Kinase 2 ◽

Thrombopoietin Receptor ◽

Src Homology ◽

Thrombopoietin Mimetic

We have identified a series of novel non-peptide compounds that activate the thrombopoietin-dependent cell line Ba/F3-huMPL. The compounds stimulated proliferation of Ba/F3-huMPL in the absence of other growth factors, but did not promote proliferation of the thrombopoietin-independent parent cell line Ba/F3. The thrombopoietin-mimetic compounds elicited signal-transduction responses comparable with recombinant human thrombopoietin, such as tyrosine phosphorylation of the thrombopoietin receptor, JAK (Janus kinase) 2, Tyk2 (tyrosine kinase 2), STAT (signal transducer and activator of transcription) 3, STAT5, MAPKs (mitogen-activated protein kinases), PLCγ (phospholipase Cγ), Grb2 (growth-factor-receptor-bound protein 2), Shc (Src homology and collagen homology), Vav, Cbl and SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) and increased the number of CD41+ cells (megakaryocyte lineage) in cultures of human CD34+ bone-marrow cells (haematopoietic stem cells). These findings suggest that this series of compounds are novel agonists of the human thrombopoietin receptor and are possible lead compounds for the generation of anti-thrombocytopaenia drugs.

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Fibroblast growth factor receptor–3 expression in meningiomas with stimulation of proliferation by the phosphoinositide 3 kinase–Akt pathway

Journal of Neurosurgery ◽

10.3171/2009.7.jns09726 ◽

2010 ◽

Vol 112 (5) ◽

pp. 934-939 ◽

Cited By ~ 19

Author(s):

Mahlon D. Johnson ◽

Mary J. O'Connell ◽

Webster Pilcher ◽

Jay E. Reeder

Keyword(s):

Cell Proliferation ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Growth Factor Receptor ◽

Fibroblast Growth ◽

Who Grade ◽

Human Meningiomas ◽

Grade Ii ◽

Meningioma Cell ◽

Phosphoinositide 3 Kinase

Object Fibroblast growth factor receptors (FGFRs)–1, –2, and –3 are expressed in the developing brain and may participate in CNS neoplasia. Fibroblast growth receptor–3 has not been demonstrated in the human CNS or its tumors. Nonetheless, it has been implicated in the pathogenesis of several other forms of neoplasia. Methods Twenty-four human meningiomas were evaluated using Western blot analysis for expression of FGFR3, its ligand acidic FGF, and concomitant phosphorylation/activation of p44/42 mitogen-activated protein kinase (MAPK), Akt, and STAT3. Mutations in exons 7 and 10 of the FGFR3 gene were analyzed by polymerase chain reaction in 10 meningiomas. Primary meningioma cells cultured from 10 human meningiomas were also treated with acidic FGF and evaluated for cell proliferation or activation/phosphorylation of p44/42 MAPK, Akt, and STAT3. Results Immunoblotting demonstrated the presence of FGFR3 in 12 (71%) of 17 primarily fibroblastic and transitional WHO Grade I meningiomas. The FGFR3 was detected in 4 (80%) of 5 WHO Grade II, and 2 of 2 Grade III tumors. Acidic FGF was detected in 3 (18%) of 17 Grade I, 1 (20%) of 5 Grade II, and 1 (50%) of 2 Grade III meningiomas. In WHO Grade I meningiomas, 3 of 6 tumors with no detectable FGFR3 had no detectable p-STAT3. In WHO Grades II and III meningiomas, FGFR3 expression was associated with p-STAT3, p-Akt, and p-p44/42 MAPK expression. No mutations were demonstrated in exons 7 or 10 by polymerase chain reaction in any meningioma. Treatment with acidic FGF, a ligand for FGFR3, stimulated meningioma cell proliferation and activation of Akt and STAT3 in primary meningioma cell cultures. Conclusions These findings suggest that FGFR3 and acidic FGF are expressed in adult human leptomeninges as well as WHO Grades I and II meningiomas. Fibroblast growth factor receptor–3 activation stimulates meningioma cell proliferation by activation of the phosphoinositide 3 kinase–Akt-PRAS40-mTOR and STAT3 pathways.

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Signaling Pathways Involved in the Regulation of mRNA Translation

Molecular and Cellular Biology ◽

10.1128/mcb.00070-18 ◽

2018 ◽

Vol 38 (12) ◽

Cited By ~ 82

Author(s):

Philippe P. Roux ◽

Ivan Topisirovic

Keyword(s):

Signaling Pathways ◽

Regulation Of Gene Expression ◽

Mrna Translation ◽

Mitogen Activated Protein Kinase ◽

Translational Machinery ◽

Mapk Pathways ◽

Mitogen Activated Protein ◽

Energy Consuming ◽

Regulate Protein ◽

Phosphoinositide 3 Kinase

ABSTRACTTranslation is a key step in the regulation of gene expression and one of the most energy-consuming processes in the cell. In response to various stimuli, multiple signaling pathways converge on the translational machinery to regulate its function. To date, the roles of phosphoinositide 3-kinase (PI3K)/AKT and the mitogen-activated protein kinase (MAPK) pathways in the regulation of translation are among the best understood. Both pathways engage the mechanistic target of rapamycin (mTOR) to regulate a variety of components of the translational machinery. While these pathways regulate protein synthesis in homeostasis, their dysregulation results in aberrant translation leading to human diseases, including diabetes, neurological disorders, and cancer. Here we review the roles of the PI3K/AKT and MAPK pathways in the regulation of mRNA translation. We also highlight additional signaling mechanisms that have recently emerged as regulators of the translational apparatus.

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