The Novel Secreted Adipokine WNT1-inducible Signaling Pathway Protein 2 (WISP2) Is a Mesenchymal Cell Activator of Canonical WNT
The Novel Secreted Adipokine WNT1-inducible Signaling Pathway Protein 2 (WISP2) Is a Mesenchymal Cell Activator of Canonical WNT
复制标题
DOI：
10.1074/jbc.m113.511964
复制
发表时间：
2014-03-07
影响因子：
4.8
通讯作者：
Smith, Ulf
中科院分区：
文献类型：
--
作者：
Grunberg, John R.;Hammarstedt, Ann;Smith, Ulf
背景：WISP2是一种由前体细胞产生的胞质分泌蛋白。结果：WISP2是分泌的，但不是胞质的，它激活典型WNT并阻止成脂分化。结论：WISP2是脂肪生成承诺和分化的重要调节因子。意义：分泌的WISP2是典型WNT和PPAR激活的一种新的调节因子。wnt1诱导信号通路蛋白2 （WISP2）主要在间充质干细胞、成纤维细胞和脂肪前体细胞中表达。它既是一种分泌蛋白，也是一种胞质蛋白，后者调节前体细胞脂肪生成承诺和BMP4对PPAR的诱导。为了检验分泌蛋白的作用，我们在NIH3T3成纤维细胞中表达了全长和截断的非分泌WISP2。分泌但未截断的WISP2通过增加-catenin水平、其核靶向磷酸化和LRP5/6磷酸化激活典型WNT通路。WNT拮抗剂DICKKOPF-1可逆转分泌WISP2的作用。分化的3T3-L1脂肪细胞也是靶细胞，其中细胞外WISP2激活典型的WNT通路，抑制Pparg和相关脂肪基因，并且与WNT3a相似，促进细胞的部分去分化和诱导肌成纤维细胞表型，激活纤维化标志物。因此，WISP2在间充质前体细胞中发挥双重作用；分泌的WISP2激活典型WNT并维持细胞处于未分化状态，而细胞质WISP2调节脂肪生成承诺。
Background: WISP2 is a cytosolic and secreted protein produced by precursor cells. Results: Secreted, but not cytosolic, WISP2 activates canonical WNT and prevents adipogenic differentiation. Conclusion: WISP2 is an important regulator of both adipogenic commitment and differentiation. Significance: Secreted WISP2 is a novel regulator of canonical WNT and PPAR activation.WNT1-inducible-signaling pathway protein 2 (WISP2) is primarily expressed in mesenchymal stem cells, fibroblasts, and adipogenic precursor cells. It is both a secreted and cytosolic protein, the latter regulating precursor cell adipogenic commitment and PPAR induction by BMP4. To examine the effect of the secreted protein, we expressed a full-length and a truncated, non-secreted WISP2 in NIH3T3 fibroblasts. Secreted, but not truncated WISP2 activated the canonical WNT pathway with increased -catenin levels, its nuclear targeting phosphorylation, and LRP5/6 phosphorylation. It also inhibited Pparg activation and the effect of secreted WISP2 was reversed by the WNT antagonist DICKKOPF-1. Differentiated 3T3-L1 adipose cells were also target cells where extracellular WISP2 activated the canonical WNT pathway, inhibited Pparg and associated adipose genes and, similar to WNT3a, promoted partial dedifferentiation of the cells and the induction of a myofibroblast phenotype with activation of markers of fibrosis. Thus, WISP2 exerts dual actions in mesenchymal precursor cells; secreted WISP2 activates canonical WNT and maintains the cells in an undifferentiated state, whereas cytosolic WISP2 regulates adipogenic commitment.