SHP-2 Modulates Interleukin-1-induced Ca2+ Flux and ERK Activation via Phosphorylation of Phospholipase Cγ1

Wang, Qin; Downey, Gregory P.; Herrera-Abreu, María Teresa; Kapùs, András; McCulloch, Christopher A.

doi:10.1074/jbc.m410462200

Cited by 30 publications

(34 citation statements)

References 40 publications

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“…Thus, Src-family kinase phosphorylation of phospholipase C␥1 mediated by SHP-2 in response to RTK activation is one candidate pathway through which SHP-2 may mediate Ca 2ϩ release. Indeed, it was shown recently that SHP-2 is required for the mobilization of Ca 2ϩ in response to interleukin-1 by a mechanism involving phospholipase C␥1 tyrosine phosphorylation (26). Our data support this idea because we show specifically that the catalytic activity of SHP-2 is required for FGF-2-induced Ca 2ϩ mobilization.…”

Section: Discussionsupporting

confidence: 87%

Gain-of-function/Noonan syndrome SHP-2/ Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling

Uhlén

Burch

Zito

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Gain-of-function mutations in SHP-2͞PTPN11 cause Noonan syndrome, a human developmental disorder. Noonan syndrome is characterized by proportionate short stature, facial dysmorphia, increased risk of leukemia, and congenital heart defects in Ϸ50% of cases. Congenital heart abnormalities are common in Noonan syndrome, but the signaling pathway(s) linking gain-of-function SHP-2 mutants to heart disease is unclear. Diverse cell types coordinate cardiac morphogenesis, which is regulated by calcium (Ca 2؉ ) and the nuclear factor of activated T-cells (NFAT). It has been shown that the frequency of Ca 2؉ oscillations regulates NFAT activity. Here, we show that in fibroblasts, Ca 2؉ oscillations in response to FGF-2 require the phosphatase activity of SHP-2. Conversely, gain-of-function mutants of SHP-2 enhanced FGF-2-mediated Ca 2؉ oscillations in fibroblasts and spontaneous Ca 2؉ oscillations in cardiomyocytes. The enhanced frequency of cardiomyocyte Ca 2؉ oscillations induced by a gain-of-function SHP-2 mutant correlated with reduced nuclear translocation and transcriptional activity of NFAT. These data imply that gain-of-function SHP-2 mutants disrupt the Ca 2؉ oscillatory control of NFAT, suggesting a potential mechanism for congenital heart defects in Noonan syndrome.calcium signaling ͉ cardiomyocytes ͉ FGF ͉ receptor tyrosine kinase signaling ͉ tyrosine phosphatases T he ubiquitously expressed src homology 2 (SH2)-containing protein tyrosine phosphatase (PTP), SHP-2 (PTPN11), regulates numerous intracellular signaling cascades that control cell proliferation, differentiation, cell survival, migration, adhesion, and apoptosis (1). SHP-2 contains two NH 2 terminus SH2 domains, a PTP domain, and a COOH terminus containing two tyrosyl phosphorylation sites (1). It is now well established that SHP-2 is required for activation of the extracellular-regulated kinases (ERKs) 1 and 2 in response to the activation of receptor tyrosine kinase (RTK) and cytokine receptors (1). The SH2 domains of SHP-2 mediate not only binding to RTKs but also scaffold proteins such as Gab-1, IRS-1, and FRS-2 (1). In virtually all cases, stimulation of SHP-2 catalysis is required for downstream signaling. The SH2 domains of SHP-2 also regulate its activation. Engagement of the NH 2 SH2 domain of SHP-2 with its cognate phosphotyrosyl protein results in its activation. The mechanism of this activation involves displacement of the NH 2 SH2 domain from the PTP domain which in the basal (unbound SH2 domain) state occludes the PTP active site. Upon NH 2 SH2 domain binding, a conformational relief of this inhibitory state is achieved and the phosphatase becomes active. Insights from the crystallographic structure of SHP-2 (2) resulted in the generation of engineered mutations at residues critical for the maintenance of the basal inactivated state of SHP-2. These mutations, within the NH 2

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Section: Discussionsupporting

confidence: 87%

Gain-of-function/Noonan syndrome SHP-2/ Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling

Uhlén

Burch

Zito

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, PLCγ is activated upon IL-1β stimulation and is required for increases in PKCδ activity, activation of ERK1/2, and expression of iNOS. This study confirmed an earlier report in gingival fibroblasts which also provided evidence supporting a requirement for PLCγ in IL-1β-dependent activation of ERK1/2 [158]. Not only is there evidence for the involvement of PLCγ in IL-1β-dependent activation of ERK1/2 in gingival fibroblasts, a series of studies by McCulloch et al also report the involvement of the traditional mediators of IL-1β signaling such as IRAK along with the non-receptor tyrosine kinase focal adhesion kinase (FAK) [104] [108] and the tyrosine phosphatase SHP2 [107].…”

Section: The Role Of Map Kinase and Protein Kinase C In Regulating Insupporting

confidence: 92%

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

Ginnan

Guikema

Halligan

et al. 2008

Free Radical Biology and Medicine

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Inflammation plays a critical role in promoting smooth muscle migration and proliferation during vascular diseases such as post-angioplasty restenosis and atherosclerosis. Another common feature of many vascular diseases is the contribution of reactive oxygen (ROS) and nitrogen (RNS) species to vascular injury. Primary sources of ROS and RNS in smooth muscle are several isoforms of NADPH oxidase (Nox) and the cytokine-regulated inducible nitric oxide (NO) synthase (iNOS). One important example of the interaction between NO and ROS is the reaction of NO with superoxide to yield peroxynitrite, which may contribute to the pathogenesis of hypertension. In this review, we discuss the literature that supports an alternate possibility: Nox-derived ROS modulate NO bioavailability by altering the expression of iNOS. We highlight data showing co-expression of iNOS and Nox in vascular smooth muscle and demonstrating the functional consequences of iNOS and Nox during vascular injury. We describe the relevant literature demonstrating that the mitogen activated protein kinases (MAP kinases) are important modulators of pro-inflammatory cytokinedependent expression of iNOS. A central hypothesis discussed is that ROS-dependent regulation of the serine/threonine kinase protein kinase Cδ (PKCδ) is essential to understanding how Nox may regulate signaling pathways leading to iNOS expression. Overall, the integration of non-phagocytic NADPHoxidase with cytokine signaling in general and in vascular smooth muscle in particular is poorly understood and merit further investigation.

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“…Coverslips were placed in a sterile microscope chamber (Attofluor; Molecular Probes, Eugene, OR) and epithelial cells loaded with 3 M Fura-2/AM (Molecular Probes) in DMEM/F12 medium at 37 ЊC, 5% CO 2 for 25 min, and then washed three times with the same medium. Dynamic changes in intracellular calcium concentration ([Ca 2ϩ ] i ) in individual cells was measured using a Nikon inverted fluorescent microscope equipped with a CCD camera (Orca; Hamamatsu, Bridgewater, NJ) as previously described in detail (32). Images were acquired and analyzed using SimplePCI software (Compix, Cranberry Township, PA).…”

Section: ؉mentioning

confidence: 99%

Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung Epithelial Cells

Suzuki

Moraes

Vachon

et al. 2005

Am J Respir Cell Mol Biol

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123

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Apoptosis of distal lung epithelial cells plays a pivotal role in the pathogenesis of acute lung injury. In this context, proteinases, either circulating or leukocyte-derived, may contribute to epithelial apoptosis and lung injury. We hypothesized that apoptosis of lung epithelial cells induced by leukocyte elastase is mediated via the proteinase activated receptor (PAR)-1. Leukocyte elastase, thrombin, and PAR-1-activating peptide, but not the control peptide, induced apoptosis in human airway and alveolar epithelial cells as assessed by increases in cytoplasmic histone-associated DNA fragments and TUNEL staining. These effects were largely prevented by a specific PAR-1 antagonist and by short interfering RNA directed against PAR-1. To ascertain the mechanism of epithelial apoptosis, we determined that PAR-1AP, thrombin, and leukocyte elastase dissipated mitochondrial membrane potential, induced translocation of cytochrome c to the cytosol, enhanced cleavage of caspase-9 and caspase-3, and led to JNK activation and Akt inhibition. In concert, these observations provide strong evidence that leukocyte elastase mediates apoptosis of human lung epithelial cells through PAR-1-dependent modulation of the intrinsic apoptotic pathway via alterations in mitochondrial permeability and by modulation of JNK and Akt.

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SHP-2 Modulates Interleukin-1-induced Ca2+ Flux and ERK Activation via Phosphorylation of Phospholipase Cγ1

Cited by 30 publications

References 40 publications

Gain-of-function/Noonan syndrome SHP-2/ Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling

Gain-of-function/Noonan syndrome SHP-2/ Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung Epithelial Cells

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