Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis

Ayada, Toranoshin; Taniguchi, Koji; Okamoto, Fuyuki; Kato, Reiko; Komune, Shizuo; Takaesu, Giichi; Yoshimura, Akihiko

doi:10.1038/onc.2008.464

Cited by 31 publications

(32 citation statements)

References 46 publications

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“…4,5-biphosphate breakdown, and inositol 1,4,5-triphosphate production, which are signaling events upstream of PKC (Ayada et al, 2009). Therefore, the results of our study suggest that L-carbocisteine suppressed Ca 21 mobilization, 4,5-biphosphate breakdown, and 1,4,5-triphosphate production.…”

Section: L-carbocisteine Is a Novel Inhibitor Of Tumor Angiogenesissupporting

confidence: 47%

Orally Administered Mucolytic Drug l-Carbocisteine Inhibits Angiogenesis and Tumor Growth in Mice

Shinya

Yokota

Nakayama

et al. 2015

J Pharmacol Exp Ther

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Angiogenesis, the formation of new blood vessels from preexisting vessels, is essential for the growth and metastasis of tumors. In this study, we found that L-carbocisteine, a widely used expectorant, potently inhibits angiogenesis in vitro and in vivo. An in vivo Matrigel plug assay revealed that L-carbocisteine (2.5 mg/kg i.p. twice daily) significantly inhibited vascular endothelial growth factor (VEGF)-induced angiogenesis. L-Carbocisteine also suppressed VEGF-stimulated proliferation, migration, and formation of capillary-like structures of human umbilical vein endothelial cells (HUVECs). We examined the signaling pathways affected in VEGF-stimulated HUVECs, and found that L-carbocisteine significantly inhibited VEGF-induced phosphorylation of phospholipase C (PLC) g, protein kinase C (PKC) m, and extracellular signal-related kinases (ERK) 1/2, which have been shown to be essential for angiogenesis. However, these inhibitory effects of L-carbocisteine were not observed in the HeLa human cervical cancer cell line. An in vivo study of Colon-26 tumor-bearing mice found that tumor volumes were significantly smaller in mice treated with L-carbocisteine (150 mg/kg administered orally twice daily) in comparison with vehicle-treated mice. However, L-carbocisteine had no direct effect on Colon-26 cell proliferation or ERK activation. Collectively, our results suggest that L-carbocisteine inhibits tumor angiogenesis by suppressing PLCg/PKC/ERK signaling.

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Section: L-carbocisteine Is a Novel Inhibitor Of Tumor Angiogenesissupporting

confidence: 47%

Orally Administered Mucolytic Drug l-Carbocisteine Inhibits Angiogenesis and Tumor Growth in Mice

Shinya

Yokota

Nakayama

et al. 2015

J Pharmacol Exp Ther

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“…Furthermore, Spry4 inhibits Ca 2+ release and activation of PKC-dependent pathways downstream of VEGF-A in human embryonic kidney cells. Interestingly, Spry4 inhibits activation of Erk downstream of VEGF-A, which is PKC 4011 RESEARCH ARTICLE Role of Sprouty3 in axonal branching dependent, but not downstream of VEGF-C, which is Ras dependent (Ayada et al, 2009). This suggests that Spry4 most likely acts via the PLC-Ca ++ and not the Ras pathway, leading to both inhibition of Ca 2+ mobilisation and inhibition of Erk activation via PKC.…”

Section: Regulation Of Branching Morphogenesis By Spry Proteinsmentioning

confidence: 99%

Characterisation of a new regulator of BDNF signalling, Sprouty3, involved in axonal morphogenesis in vivo

et al. 2010

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SUMMARYDuring development, many organs, including the kidney, lung and mammary gland, need to branch in a regulated manner to be functional. Multicellular branching involves changes in cell shape, proliferation and migration. Axonal branching, however, is a unicellular process that is mediated by changes in cell shape alone and as such appears very different to multicellular branching. Sprouty (Spry) family members are well-characterised negative regulators of Receptor tyrosine kinase (RTK) signalling. Knockout of Spry1, 2 and 4 in mouse result in branching defects in different organs, indicating an important role of RTK signalling in controlling branching pattern. We report here that Spry3, a previously uncharacterised member of the Spry family plays a role in axonal branching. We found that spry3 is expressed specifically in the trigeminal nerve and in spinal motor and sensory neurons in a Brain-derived neurotrophin factor (BDNF)-dependent manner. Knockdown of Spry3 expression causes an excess of axonal branching in spinal cord motoneurons in vivo. Furthermore, Spry3 inhibits the ability of BDNF to induce filopodia in Xenopus spinal cord neurons. Biochemically, we show that Spry3 represses calcium release downstream of BDNF signalling. Altogether, we have found that Spry3 plays an important role in the regulation of axonal branching of motoneurons in vivo, raising the possibility of unexpected conservation in the involvement of intracellular regulators of RTK signalling in multicellular and unicellular branching.

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“…However, Spry4 overexpression decreases VEGF-A-mediated hydrolysis of PtdIns(4,5)P 2 , thereby decreasing the formation of inositol1,4,5-trisphosphate and diacylglycerol with a resultant decrease in elevation of intracellular Ca 2ϩ concentrations and activation of protein kinase C. This action of Spry4 probably results from binding of PtdIns(4,5)P 2 to the C terminus of Spry4, thereby limiting or altering substrate availability to PLC (Ayada et al, 2009). As with all overexpression studies, the physiological significance of these findings remain to be determined.…”

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confidence: 99%

Intermolecular Interactions of Sprouty Proteins and Their Implications in Development and Disease

Edwin

Anderson²,

Ying³

et al. 2009

Mol Pharmacol

103

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Receptor tyrosine kinase (RTK) signaling is spatially and temporally regulated by a number of positive and negative regulatory mechanisms. These regulatory mechanisms control the amplitude and duration of the signals initiated at the cell surface to have a normal or aberrant biological outcome in development and disease, respectively. In the past decade, the Sprouty (Spry) family of proteins has been identified as modulators of RTK signaling in normal development and disease. This review summarizes recent advances concerning the biological activities modulated by Spry family proteins, their interactions with signaling proteins, and their involvement in cardiovascular diseases and cancer. The diversity of mechanisms in the regulation of Spry expression and activity in cell systems emphasizes the crucial role of Spry proteins in development and growth across the animal kingdom.The Sprouty (Spry) protein was first described by Hacohen et al. (1998) as an inhibitor of fibroblast growth factor (FGF)-stimulated tracheal branching during Drosophila melanogaster development. Subsequent work established D. melanogaster Spry (dSpry) as a widespread inhibitor of receptor-tyrosine kinase (RTK) signaling during organogenesis. For example, spry-null flies or flies harboring loss of function mutations on spry exhibit eye and wing phenotypes indicative of uncontrolled epidermal growth factor receptor (EGFR) signaling (Minowada et al., 1999).Four mammalian spry genes have been defined based on sequence similarity with dSpry. Three homologs of dSpry were first identified in a search of the human expressed

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Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis

Cited by 31 publications

References 46 publications

Orally Administered Mucolytic Drug l-Carbocisteine Inhibits Angiogenesis and Tumor Growth in Mice

Orally Administered Mucolytic Drug l-Carbocisteine Inhibits Angiogenesis and Tumor Growth in Mice

Characterisation of a new regulator of BDNF signalling, Sprouty3, involved in axonal morphogenesis in vivo

Intermolecular Interactions of Sprouty Proteins and Their Implications in Development and Disease

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