Division of Rheumatology, Department of Medicine, University of Washington, 750 Republican St, Seattle, WA 98019, USA.
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115, USA.
Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1516-1524. doi: 10.1016/j.bbadis.2019.03.001. Epub 2019 Mar 13.
Cadherins are homophilic cell-to-cell adhesion molecules that help cells respond to environmental changes. Newly formed cadherin junctions are associated with increased cell phosphorylation, but the pathways driving this signaling response are largely unknown. Since cadherins have no intrinsic signaling activity, this phosphorylation must occur through interactions with other signaling molecules. We previously reported that cadherin-11 engagement activates joint synovial fibroblasts, promoting inflammatory and degradative pathways important in rheumatoid arthritis (RA) pathogenesis. Our objective in this study was to discover interacting partners that mediate cadherin-11 signaling. Protein array screening showed that cadherin-11 extracellular binding domains linked to an Fc domain (cad11Fc) induced platelet-derived growth factor (PDGFR)-α phosphorylation in synovial fibroblasts and glioblastoma cells. PDGFRs are growth factor receptor tyrosine kinases that promote cell proliferation, survival, and migration in mesodermally derived cells. Increased PDGFR activity is implicated in RA pathology and associates with poor prognosis in several cancers, including sarcoma and glioblastoma. PDGFRα activation by cadherin-11 signaling promoted fibroblast proliferation, a signaling pathway independent from cadherin-11-stimulated IL-6 or matrix metalloproteinase (MMP)-3 release. PDGFRα phosphorylation mediated most of the cad11Fc-induced phosphatidyl-3-kinase (PI3K)/Akt activation, but only part of the mitogen-activated protein kinase (MAPK) response. PDGFRα-dependent signaling did not require cell cadherin-11 expression. Rather, cad11Fc immunoprecipitated PDGFRα, indicating a direct interaction between cadherin-11 and PDGFRα extracellular domains. This study is the first to report an interaction between cadherin-11 and PDGFRα and adds to our growing understanding that cadherin-growth factor receptor interactions help balance the interplay between tissue growth and adhesion.
钙黏蛋白是同种细胞间的黏附分子，有助于细胞对外界环境变化做出反应。新形成的钙黏蛋白连接点与细胞磷酸化增加有关，但驱动这种信号反应的途径在很大程度上仍是未知的。由于钙黏蛋白本身没有信号活性，这种磷酸化必须通过与其他信号分子的相互作用来实现。我们之前曾报道过，钙黏蛋白-11 的结合可激活关节滑膜成纤维细胞，促进在类风湿关节炎（RA）发病机制中起重要作用的炎症和降解途径。我们本研究的目的是发现介导钙黏蛋白-11 信号的相互作用伙伴。蛋白质阵列筛选表明，钙黏蛋白-11 细胞外结合域与 Fc 结构域（cad11Fc）相连，可诱导滑膜成纤维细胞和神经胶质瘤细胞中血小板衍生生长因子（PDGFR）-α 的磷酸化。PDGFR 是生长因子受体酪氨酸激酶，可促进中胚层来源的细胞增殖、存活和迁移。PDGFR 活性增加与 RA 病理有关，并与包括肉瘤和神经胶质瘤在内的几种癌症的不良预后相关。钙黏蛋白-11 信号转导通过 PDGFRα 的激活促进成纤维细胞增殖，这是一种独立于钙黏蛋白-11 刺激的白细胞介素-6 或基质金属蛋白酶（MMP）-3 释放的信号通路。PDGFRα 磷酸化介导了 cad11Fc 诱导的大部分磷脂酰肌醇-3-激酶（PI3K）/Akt 激活，但只介导了一部分丝裂原激活蛋白激酶（MAPK）反应。PDGFRα 依赖性信号转导不需要细胞钙黏蛋白-11 的表达。相反，cad11Fc 免疫沉淀 PDGFRα，表明钙黏蛋白-11 和 PDGFRα 细胞外结构域之间存在直接相互作用。本研究首次报道了钙黏蛋白-11 和 PDGFRα 之间的相互作用，并增加了我们对钙黏蛋白-生长因子受体相互作用有助于平衡组织生长和黏附之间相互作用的理解。
