corkscrew encodes a putative protein tyrosine phosphatase that functions to transduce the terminal signal from the receptor tyrosine kinase torso

Perkins, Lizabeth A.; Larsen, Inger Kristin; Perrimon, Norbert

doi:10.1016/0092-8674(92)90098-w

Cited by 384 publications

(240 citation statements)

References 66 publications

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“…SHP-1 is highly expressed in hematopoietic cells and negatively regulates hematopoietic signaling pathways downstream of cytokine receptors, oligomeric receptors, such as antigen and Fc receptors, and RTKs (Tonks and Neel, 1996). SHP-2 is expressed ubiquitously and may play as a positive regulator of receptor signaling pathways (Perkins et al, 1992;Tomic et al, 1995). Cpd 5, the prototype K vitamin analog, has been shown to induce EGFR hyper-phosphorylation, which is not due to EGFR kinase activation, but rather is the consequence of the inhibition of EGFR tyrosine-phosphatase(s) (Ni et al, 1998;Nishikawa et al, 1999;Wang et al, 2000).…”

Section: Prolonged Egfr Hyper-phosphorylation and Nuclear Translocatimentioning

confidence: 99%

K vitamins, PTP antagonism, and cell growth arrest

Carr

Wang

Kar

2002

Journal Cellular Physiology

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The main function of K vitamins is to act as co-factors for g-glutamyl carboxylase. However, they have also recently been shown to inhibit cell growth. We have chemically synthesized a series of K vitamin analogs with various side chains at the 2 or 3 position of the core naphthoquinone structure. The analogs with short thio-ethanol side chains are found to be more potent growth inhibitors in vitro of various tumor cell lines. Cpd 5 or [2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone] is one of the most potent. The anti-proliferation activity of these compounds is antagonized by exogenous thiols but not by non-thiol antioxidants. This suggests that the growth inhibition is mediated by sulfhydryl arylation of cellular glutathione and cysteine-containing proteins and not by oxidative stress. The protein tyrosine phosphatases (PTP) are an important group of proteins that contain cysteine at their catalytic site. PTPs regulate mitogenic signal transduction and cell cycle progression. PTP inhibition by Cpd 5 results in prolonged tyrosine phosphorylation and activation of several kinases and transcription factors including EGFR, ERK1/2, and Elk1. Cpd 5 could activate ERK1/2 either by signaling from an activated EGFR, which is upstream in the signaling cascade, or by direct inhibition of ERK1/2 phosphatase(s). Prolonged ERK1/2 phosphorylation strongly correlates with Cpd 5-mediated growth inhibition. Cpd 5 can also bind to and inhibit the Cdc25 family of dual specific phosphatases. As a result, several Cdc25 substrates (Cdk1, Cdk2, Cdk4) involved in cell cycle progression are tyrosine phosphorylated and thereby inhibited by its action. Cpd 5 could also inhibit both normal liver regeneration and hepatoma growth in vivo. DNA synthesis during rat liver regeneration following partial hepatectomy, transplantable rat hepatoma cell growth, and glutathione-S-transferase-pi expressing hepatocytes after administration of the chemical carcinogen diethylnitrosamine, are all inhibited by Cpd 5 administration. The growth inhibitory effect during liver regeneration and transplantable tumor growth is also correlated with ERK1/2 phosphorylation induced by Cpd 5. Thus, Cpd 5-mediated inhibition of PTPs, such as Cdc25 leads to cell growth arrest due to altered activity of key cellular kinases involved in signal transduction and cell cycle progression. This prototype K vitamin analog represents a novel class of growth inhibitor based upon its action as a selective PTP antagonist. It is clearly associated with prolonged ERK1/2 phosphorylation, which is in contrast with the transient ERK1/2 phosphorylation induced by growth stimulatory mitogens.

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Section: Prolonged Egfr Hyper-phosphorylation and Nuclear Translocatimentioning

confidence: 99%

K vitamins, PTP antagonism, and cell growth arrest

Carr

Wang

Kar

2002

Journal Cellular Physiology

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“…PTP1D, also known as SHPTP2, PTP2C, and Syp, is ubiquitously expressed as is the homologue in Drosophila, csw (28). Genetic analysis indicates that Csw is required for signaling by Torso (29). Likewise, vertebrate PTP1D has been implicated in positive signaling by the insulin receptor (26), the epidermal growth factor receptor (30) and the fibroblast growth factor receptor (25).…”

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confidence: 99%

The SH2 Domain-containing Tyrosine Phosphatase PTP1D Is Required for Interferon α/β-induced Gene Expression

David

Zhou

Pine³

et al. 1996

Journal of Biological Chemistry

100

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Interferons (IFNs) induce early response genes by stimulating Janus family (Jak) tyrosine kinases, leading to tyrosine phosphorylation of Stat (signal transducer and activator of transcription) proteins. Previous studies demonstrated that a protein-tyrosine phosphatase (PTP) is required for activation of the ISGF3 transcription complex by IFN␣/␤, but the specific PTP responsible remained unidentified. We now show that the SH2 domain containing tyrosine phosphatase PTP1D (also designated as SHPTP2, SHPTP3, PTP2C, or Syp) is constitutively associated with the IFN␣/␤ receptor and becomes tyrosine-phosphorylated in response to ligand. Furthermore, transient expression of a phosphatase-inactive mutant or the COOH-terminal SH2 domain of PTP1D causes a dominant negative effect on IFN␣/␤-induced early response gene expression. These results provide strong evidence that PTP1D functions as a positive regulator of the IFN␣/␤-induced Jak/Stat signal transduction pathway.Interferons as well as many other cytokines and growth factors stimulate the expression of early response genes by inducing the tyrosine phosphorylation of SH2-containing transcription factors termed Stats (1-5), a process that involves the activation and tyrosine phosphorylation of members of the Janus family of protein-tyrosine kinases (Jaks) (6 -9). Tyrosine phosphorylation of the Stat proteins causes them to either homo-or heterodimerize and to translocate to the nucleus, where they interact with enhancer elements in a variety of promoters to initiate transcription (10,11). Serine phosphorylation of Stat1 by mitogen-activated protein kinase (MAPK, ERK2) is required in addition to tyrosine phosphorylation for maximum transcriptional activation (12, 13).Several components of the IFN␣/␤ 1 signaling pathway have been identified and molecularly cloned, such as the two subunits (␣ and ␤) of the IFN␣/␤ receptor (14 -16). Binding of IFN␣/␤ to its receptor causes the rapid activation of the Jak tyrosine kinases Jak1 and Tyk2 (6, 7) which results in tyrosine phosphorylation of both Stat1␣ (p91) and Stat2 (p113) (1,17) and the formation of at least two transcription factor complexes. One complex, composed of a heterotrimer of Stat1␣, Stat2, and the DNA binding component p48 (ISGF3␥), binds to interferon-stimulated response elements (ISREs) (18,19), whereas Stat1␣ homodimers bind to ␥ response region (GRR) elements (20).Although much attention has been devoted to the tyrosine kinases involved in Stat activation, the role of tyrosine phosphatases in IFN␣/␤ signal transduction is less understood. Evidence from both in vitro and in vivo studies indicated that tyrosine phosphatases can act as positive as well as negative regulators of the IFN␣/␤-induced Jak/Stat pathway (17,21,22). Recently, we were able to demonstrate that the SH2 domain containing tyrosine phosphatase PTP1C (SHPTP1, HCP, or SHP) functions as a suppressor of IFN␣/␤ signal transduction in hematopoietic cells by specific down-modulation of Jak1 tyrosine phosphorylation (23). Studies of Stat activation by...

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“…Par exemple, le groupe de Norbert Perrimon distingua une composante à action positive en aval du RTK Torso (TOR), nommée CSW (corkscrew ; aussi appelée SHP-2), une tyrosine phosphatase comprenant deux domaines SH2 (src homology-2) [11]. La fonction de SHP-2 dans la voie RAS/ERK demeura nébuleuse jusqu'à l'identification d'une autre protéine agissant entre les RTK et RAS, nommée DOS (daugther of sevenless), homologue des GAB (GRB2-associated binding protein) de mammifères, une protéine à domaine PH (pleckstrin homology) [12].…”

Section: Apport Des Modèles Génétiquesunclassified

La signalisation RTK/RAS/ERK élargie

Ashton‐Beaucage

Therrien

2010

Med Sci (Paris)

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corkscrew encodes a putative protein tyrosine phosphatase that functions to transduce the terminal signal from the receptor tyrosine kinase torso

Cited by 384 publications

References 66 publications

K vitamins, PTP antagonism, and cell growth arrest

K vitamins, PTP antagonism, and cell growth arrest

The SH2 Domain-containing Tyrosine Phosphatase PTP1D Is Required for Interferon α/β-induced Gene Expression

La signalisation RTK/RAS/ERK élargie

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