Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, 187-8502, Japan.
Genes Cells. 2014 Jan;19(1):66-77. doi: 10.1111/gtc.12108. Epub 2013 Nov 20.
After peripheral nerve injury, Schwann cells gain a migratory phenotype and remodel their extracellular matrix to provide a supportive environment for axonal regeneration. The soluble neuregulin-1 isoform, that is, glial growth factor (GGF), is expressed in regenerating axons of injured peripheral nerves and regulates Schwann cell motility by activating the ErbB family of tyrosine kinase receptors, but how GGF/ErbB signaling contributes to Schwann cell motility remains unclear. Here, we show that GGF stimulates Schwann cell migration by inducing the formation of a protein complex containing the fibronectin receptor α5β1 integrin, ErbB2, and focal adhesion kinase (FAK). ErbB2 co-localizes and co-immunoprecipitates with the focal complex members including α5β1 integrin and FAK after GGF treatment. These effects of GGF appear to involve FAK activation, which occurs downstream of ErbB2 stimulation. RNAi-mediated down-regulation of α5 integrin expression in primary cultured Schwann cells resulted in significantly decreased interaction between FAK and ErbB2, as well as decreased GGF-induced migration. An increase in the α5β1 integrin-ErbB2-FAK complex formation was observed in injured nerve Schwann cells, but not uninjured control. Taken together, these data suggest that GGF plays an important modulatory role in Schwann cell migration after nerve crush by inducing α5β1 integrin-ErbB2-FAK complex formation.
外周神经损伤后，许旺细胞获得迁移表型，并重塑细胞外基质，为轴突再生提供支持环境。可溶性神经调节素-1 同种型，即胶质细胞生长因子（GGF），在外周神经损伤后的再生轴突中表达，并通过激活表皮生长因子受体（ErbB）家族酪氨酸激酶受体来调节许旺细胞的迁移，但 GGF/ErbB 信号如何促进许旺细胞的迁移尚不清楚。在这里，我们表明 GGF 通过诱导包含纤连蛋白受体α5β1 整联蛋白、ErbB2 和粘着斑激酶（FAK）的蛋白质复合物的形成来刺激许旺细胞迁移。GGF 处理后，ErbB2 与粘着斑复合物成员包括α5β1 整联蛋白和 FAK 共定位并共免疫沉淀。GGF 的这些作用似乎涉及 FAK 的激活，FAK 的激活发生在 ErbB2 刺激的下游。在原代培养的许旺细胞中，用 RNAi 下调α5 整联蛋白表达，导致 FAK 与 ErbB2 之间的相互作用以及 GGF 诱导的迁移显著减少。在损伤神经许旺细胞中观察到α5β1 整联蛋白-ErbB2-FAK 复合物形成增加，但在未损伤对照中没有观察到。总之，这些数据表明，GGF 通过诱导α5β1 整联蛋白-ErbB2-FAK 复合物形成，在外周神经挤压后对许旺细胞迁移发挥重要的调节作用。
