Ratcliffe Colin D H, Sahgal Pranshu, Parachoniak Christine A, Ivaska Johanna, Park Morag
Department of Biochemistry, McGill University, Montreal, Quebec, H3G 1Y6, Canada.
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, H3A 1A3, Canada.
Traffic. 2016 Jun;17(6):670-88. doi: 10.1111/tra.12390. Epub 2016 Apr 5.
The integrin family of cell adhesion receptors link extracellular matrices to intracellular signaling pathways and the actin cytoskeleton; and regulate cell migration, proliferation and survival in normal and diseased tissues. The subcellular location of integrin receptors is critical for their function and deregulated trafficking is implicated in various human diseases. Here we identify a role for Golgi-localized gamma-ear containing Arf-binding protein 3 (GGA3), in regulating trafficking of β1 integrin. GGA3 knockdown reduces cell surface and total levels of α2, α5 and β1 integrin subunits, inhibits cell spreading, reduces focal adhesion number, as well as cell migration. In the absence of GGA3, integrins are increasingly retained inside the cell, traffic toward the perinuclear lysosomal compartment and their degradation is enhanced. Integrin traffic and maintenance of integrin levels are dependent on the integrity of the Arf binding site of GGA3. Furthermore, sorting nexin 17 (SNX17), a critical regulator of integrin recycling, becomes mislocalized to enlarged late endosomes upon GGA3 depletion. These data support a model whereby GGA3, through its ability to regulate SNX17 endosomal localization and through interaction with Arf6 diverts integrins from the degradative pathway supporting cell migration.
细胞黏附受体的整合素家族将细胞外基质与细胞内信号通路及肌动蛋白细胞骨架相连；并在正常组织和患病组织中调节细胞迁移、增殖和存活。整合素受体的亚细胞定位对其功能至关重要，而失调的运输与多种人类疾病有关。在这里，我们确定了高尔基体定位的含γ耳的Arf结合蛋白3（GGA3）在调节β1整合素运输中的作用。GGA3基因敲低会降低α2、α5和β1整合素亚基的细胞表面水平和总水平，抑制细胞铺展，减少粘着斑数量以及细胞迁移。在没有GGA3的情况下，整合素越来越多地滞留在细胞内，向核周溶酶体区室运输，其降解增强。整合素运输和整合素水平的维持依赖于GGA3的Arf结合位点的完整性。此外，分选连接蛋白17（SNX17）是整合素循环的关键调节因子，在GGA3缺失时会错误定位到扩大的晚期内体。这些数据支持了一种模型，即GGA3通过其调节SNX17内体定位的能力以及通过与Arf6相互作用，将整合素从支持细胞迁移的降解途径中转移出来。
