Opposite effects of dihydrosphingosine 1-phosphate and sphingosine 1-phosphate on transforming growth factor-β/Smad signaling are mediated through the PTEN/PPM1A-dependent pathway
Opposite effects of dihydrosphingosine 1-phosphate and sphingosine 1-phosphate on transforming growth factor-β/Smad signaling are mediated through the PTEN/PPM1A-dependent pathway
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DOI：
10.1074/jbc.m802417200
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发表时间：
2008-07-11
影响因子：
4.8
通讯作者：
Trojanowska, Maria
中科院分区：
文献类型：
--
作者：
Bu, Shizhong;Kapanadze, Bagrat;Trojanowska, Maria
转化生长因子-β（TGF-β）是生理性结缔组织生物合成的重要调节剂，并且在病理性组织纤维化中起核心作用。以前的研究已经确定，一种生物活性脂质介质，鞘氨醇1-磷酸（S1 P），通过交叉激活Smad信号传导模拟TGF-β的一些促纤维化功能。在这里，我们报告，鞘氨醇激酶的另一种产品，二氢鞘氨醇1-磷酸（dhS 1 P），在TGF-β信号的调节中具有相反的作用。与S1 P相反，dhS 1 P抑制TGF-β诱导的Smad 2/3磷酸化和胶原合成的上调。dhS 1 P的作用需要一种脂质磷酸酶，PTEN，一种细胞生长和存活的关键调节剂。dhS 1 P刺激PTEN的C-末端结构域的磷酸化及其随后易位到细胞核中。我们证明了一个新的功能，核PTEN作为一个辅助因子的Smad 2/3磷酸酶，PPM 1A。PTEN与PPM 1A的复合物形成不需要脂质磷酸酶活性，而是依赖于位于PTEN的C-末端结构域中的丝氨酸/苏氨酸残基的磷酸化。在与PTEN形成复合物后，PPM 1A被保护免于由TGF-β信号传导诱导的降解。因此，PTEN的过表达消除了TGF-β诱导的Smad 2/3磷酸化。这项研究建立了一个新的作用，核PTEN的稳定PPM 1A。PTEN介导的鞘脂和TGF-β信号传导途径之间的串扰可能在生理和病理TGF-β信号传导中起重要作用。
Transforming growth factor-beta (TGF-beta) is an important regulator of physiological connective tissue biosynthesis and plays a central role in pathological tissue fibrosis. Previous studies have established that a biologically active lipid mediator, sphingosine 1-phosphate (S1P), mimics some of the profibrotic functions of TGF-beta through cross-activation of Smad signaling. Here we report that another product of sphingosine kinase, dihydrosphingosine 1-phosphate (dhS1P), has an opposite role in the regulation of TGF-beta signaling. In contrast to S1P, dhS1P inhibits TGF-beta-induced Smad2/3 phosphorylation and up-regulation of collagen synthesis. The effects of dhS1P require a lipid phosphatase, PTEN, a key modulator of cell growth and survival. dhS1P stimulates phosphorylation of the C-terminal domain of PTEN and its subsequent translocation into the nucleus. We demonstrate a novel function of nuclear PTEN as a co-factor of the Smad2/3 phosphatase, PPM1A. Complex formation of PTEN with PPM1A does not require the lipid phosphatase activity but depends on phosphorylation of the serine/threonine residues located in the C-terminal domain of PTEN. Upon complex formation with PTEN, PPM1A is protected from degradation induced by the TGF-beta signaling. Consequently, overexpression of PTEN abrogates TGF-beta-induced Smad2/3 phosphorylation. This study establishes a novel role for nuclear PTEN in the stabilization of PPM1A. PTEN-mediated cross-talk between the sphingolipid and TGF-beta signaling pathways may play an important role in physiological and pathological TGF-beta signaling.