Abstract
Signaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion. Furthermore, IFT20 promotes the efficiency of transport through the Golgi complex. These findings shed new insights into how Ror2 signaling promotes tumor invasiveness, and also advance the understanding of how Golgi structure and transport can be regulated.
Highlights
In this setting, we have previously shown that the expression of both Wnt5a and Ror[2] is dependent, at least in part, on the epithelial-to-mesenchymal transition (EMT)-related transcription factor Snail in human osteosarcoma SaOS2 cells[16]
We examined whether intraflagellar transport 20 (IFT20) regulates the Golgi structure in other tumor cells whose invasiveness might be promoted by the constitutive activation of Ror[2] signaling
As IFT20 resides at the cis-side of the Golgi (Supplementary Fig. 2), we examined whether IFT20 interacts with AKAP450, a molecule that recruits γ-tubulin ring complex (γ-TuRC) to the cis-Golgi by forming a complex with GM130 27
Summary
We have previously shown that the expression of both Wnt5a and Ror[2] is dependent, at least in part, on the epithelial-to-mesenchymal transition (EMT)-related transcription factor Snail in human osteosarcoma SaOS2 cells[16]. MMPs are targeted to discrete structures on the surface of tumor cells, known as invadopodia, which provide a way of concentrating and targeting MMPs to specific sites of the ECM in promoting tumor invasion[18, 19] To achieve these properties of tumor invasion, the intracellular transport of proteins and membranes to the cell surface must be polarized. Multiple tumor types lose their cilium during transformation, but IFT20 is still expressed in these non-ciliated tumor cells What role it may play remains unclear. We uncover a new non-ciliary role of IFT20, acting to regulate Golgi structure and transport, and find that this role mediates the ability of constitutively activated Ror[2] signaling to promote tumor invasiveness.
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