The LDL receptor-related protein 1 (LRP1) regulates the PDGF signaling pathway by binding the protein phosphatase SHP-2 and modulating SHP-2- mediated PDGF signaling events.
The LDL receptor-related protein 1 (LRP1) regulates the PDGF signaling pathway by binding the protein phosphatase SHP-2 and modulating SHP-2- mediated PDGF signaling events.
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DOI：
10.1371/journal.pone.0070432
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Strickland DK
中科院分区：
文献类型：
--
作者：
Craig J;Mikhailenko I;Noyes N;Migliorini M;Strickland DK
PDGF信号通路在几个生物系统中起主要作用，包括经皮腔内冠状动脉成形术后发生的血管重塑。最近的研究表明，LDL受体相关蛋白1（LRP 1）是PDGF信号通路的生理调节剂。这种调节如何发生的基本机制细节还有待解决。PDGF受体β（PDGFRβ）的激活导致内体内LRP 1胞质结构域的酪氨酸磷酸化，并产生对信号传导途径中涉及的衔接蛋白（如SHP-2）亲和力增加的LRP 1分子。SHP-2是一种正调节PDGFRβ通路的蛋白酪氨酸磷酸酶，是PDGF介导的趋化性所必需的。我们研究了LRP 1可能通过结合SHP-2并与PDGFRβ竞争该分子来调节PDGFRβ信号通路的可能性。为了定量SHP-2和磷酸化形式的LRP 1胞内结构域之间的相互作用，我们利用纯化的重组蛋白的ELISA。这些研究揭示了SHP-2与LRP 1胞内结构域和PDGFRβ激酶结构域的磷酸化形式的高亲和力结合。通过使用充分表征的发动蛋白抑制剂dynasore，我们确定PDGF诱导的SHP-2磷酸化主要发生在内体区室中，与LRP 1被激活的PDGFRβ酪氨酸磷酸化的区室相同。免疫荧光研究揭示了PDGF刺激成纤维细胞后LRP 1和磷酸化SHP-2的共定位。为了确定LRP 1对SHP-2介导的PDGF趋化性的贡献，我们采用了表达LRP 1且LRP 1缺陷的成纤维细胞和特异性SHP-2抑制剂NSC-87877。我们的研究结果表明，LRP 1调节SHP-2介导的PDGF介导的趋化性。我们的数据表明，磷酸化形式的LRP 1和PDGFRβ竞争SHP-2结合，LRP 1的表达减弱SHP-2介导的PDGF信号传导事件。
The PDGF signaling pathway plays a major role in several biological systems, including vascular remodeling that occurs following percutaneous transluminal coronary angioplasty. Recent studies have shown that the LDL receptor-related protein 1 (LRP1) is a physiological regulator of the PDGF signaling pathway. The underlying mechanistic details of how this regulation occurs have yet to be resolved. Activation of the PDGF receptor β (PDGFRβ) leads to tyrosine phosphorylation of the LRP1 cytoplasmic domain within endosomes and generates an LRP1 molecule with increased affinity for adaptor proteins such as SHP-2 that are involved in signaling pathways. SHP-2 is a protein tyrosine phosphatase that positively regulates the PDGFRβ pathway, and is required for PDGF-mediated chemotaxis. We investigated the possibility that LRP1 may regulate the PDGFRβ signaling pathway by binding SHP-2 and competing with the PDGFRβ for this molecule. To quantify the interaction between SHP-2 and phosphorylated forms of the LRP1 intracellular domain, we utilized an ELISA with purified recombinant proteins. These studies revealed high affinity binding of SHP-2 to phosphorylated forms of both LRP1 intracellular domain and the PDGFRβ kinase domain. By employing the well characterized dynamin inhibitor, dynasore, we established that PDGF-induced SHP-2 phosphorylation primarily occurs within endosomal compartments, the same compartments in which LRP1 is tyrosine phosphorylated by activated PDGFRβ. Immunofluorescence studies revealed colocalization of LRP1 and phospho-SHP-2 following PDGF stimulation of fibroblasts. To define the contribution of LRP1 to SHP-2-mediated PDGF chemotaxis, we employed fibroblasts expressing LRP1 and deficient in LRP1 and a specific SHP-2 inhibitor, NSC-87877. Our results reveal that LRP1 modulates SHP-2-mediated PDGF-mediated chemotaxis. Our data demonstrate that phosphorylated forms of LRP1 and PDGFRβ compete for SHP-2 binding, and that expression of LRP1 attenuates SHP-2-mediated PDGF signaling events.
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影响因子：
3.7
作者：
Boucher, Philippe;Li, Wei-Ping;Matz, Rachel L.;Takayama, Yoshiharu;Auwerx, Johan;Anderson, Richard G. W.;Herz, Joachim
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通讯作者：
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