Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis
Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis
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DOI：
10.1038/onc.2008.464
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发表时间：
2009-02-01
期刊：
影响因子：
8
通讯作者：
Yoshimura, A.
中科院分区：
文献类型：
--
作者：
Ayada, T.;Taniguchi, K.;Yoshimura, A.
Sproutys已被证明负调节生长因子诱导的细胞外信号调节激酶（ERK）的激活，并建议是一种抑癌基因。然而，抑制的分子机制尚未完全阐明。Sprouty 4抑制血管内皮生长因子（VEGF）-A诱导的ERK激活，但不抑制VEGF-C诱导的ERK激活。研究表明，VEGF-A介导的ERK激活强烈依赖于蛋白激酶C（PKC），而VEGF-C介导的ERK激活依赖于Ras。这表明Sprouty 4比Ras途径更特异性地抑制PKC途径。在这项研究中，我们证实Sprouty 4抑制PKC下游的各种信号，如MARCKS和蛋白激酶D（PKD）的磷酸化，以及PKC依赖的核因子（NF）-κ B B激活。此外，Sprouty 4抑制PKC的上游信号，例如响应VEGF-A的Ca 2+动员、磷脂酰肌醇4，5-二磷酸（PIP 2）分解和肌醇1，4，5-三磷酸（IP 3）产生。这些作用依赖于C-末端富含半胱氨酸的区域，但不依赖于Sprouty 4的N-末端区域，这对于抑制成纤维细胞生长因子（FGF）介导的ERK活化至关重要。Sprouty 4过表达或Sprouty 4基因的缺失不影响磷脂酶C（PLC）γ-1活化，其是催化PIP 2水解的酶。此外，Sprouty 4不仅抑制VEGF-A介导的PIP 2水解，而且还抑制溶血磷脂酸（LPA）诱导的PIP 2分解，该分解由G蛋白偶联受体（GPCR）激活的PLC β/β催化。总之，Sprouty 4对各种刺激具有比以前认为的更广泛的抑制活性;它可以作为各种类型的PLC依赖性信号传导以及ERK激活的抑制剂。
Sproutys have been shown to negatively regulate growth factor-induced extracellular signal-regulated kinase (ERK) activation, and suggested to be an anti-oncogene. However, molecular mechanism of the suppression has not yet been clarified completely. Sprouty4 inhibits vascular endothelial growth factor (VEGF)-A-induced ERK activation, but not VEGF-C-induced ERK activation. It has been shown that VEGF-A-mediated ERK activation is strongly dependent on protein kinase C (PKC), whereas that by VEGF-C is dependent on Ras. This suggests that Sprouty4 inhibits the PKC pathway more specifically than the Ras pathway. In this study, we confirmed that Sprouty4 suppressed various signals downstream of PKC, such as phosphorylation of MARCKS and protein kinase D (PKD), as well as PKC-dependent nuclear factor (NF)-kappa B activation. Furthermore, Sprouty4 suppressed upstream signals of PKC, such as Ca2+ mobilization, phosphatidylinositol 4,5-biphosphate (PIP2) breakdown and inositol 1,4,5-triphosphate (IP3) production in response to VEGF-A. Those effects were dependent on the C-terminal cysteine-rich region, but not on the N-terminal region of Sprouty4, which is critical for the suppression of fibroblast growth factor (FGF)-mediated ERK activation. Sprouty4 overexpression or deletion of the Sprouty4 gene did not affect phospholipase C (PLC) gamma-1 activation, which is an enzyme that catalyzes PIP2 hydrolysis. Moreover, Sprouty4 inhibited not only VEGF-A-mediated PIP2 hydrolysis but also inhibited the lysophosphatidic acid (LPA)-induced PIP2 breakdown that is catalyzed by PLC beta/epsilon activated by G-protein coupled receptor (GPCR). Taken together, Sprouty4 has broader suppression activity for various stimuli than previously thought; it may function as an inhibitor for various types of PLC-dependent signaling as well as for ERK activation.