TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis
| Autor: | Shanmugam Panneer Selvam, Can E. Senkal, Raquela J. Thomas, Salih Gencer, Jisun Kim, Philip H. Howe, Rose Nganga, Natalia V. Oleinik, Mohammed Dany, Ryan M. De Palma, Besim Ogretmen |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Ceramide Biology Ceramides Biochemistry Article Smad7 Protein 03 medical and health sciences chemistry.chemical_compound Mice Intraflagellar transport Cell Movement Cell Line Tumor Sphingosine N-Acyltransferase Animals Humans Cilia Neoplasm Metastasis Molecular Biology Ceramide synthase Cell Proliferation Mice Knockout Cell growth Cell migration Cell Biology Sphingolipid Cell biology Disease Models Animal 030104 developmental biology chemistry A549 Cells Gene Knockdown Techniques Cancer cell Smoothened Receptors Transforming Growth Factor beta |
| Zdroj: | Science signaling. 10(502) |
| ISSN: | 1937-9145 |
| Popis: | Signaling by the transforming growth factor–β (TGF-β) receptors I and II (TβRI/II) and the primary cilia-localized sonic hedgehog (Shh) pathway promote cell migration and, consequently, tumor metastasis. In contrast, the sphingolipid ceramide inhibits cell proliferation and tumor metastasis. We investigated whether ceramide metabolism inhibited TβRI/II trafficking to primary cilia to attenuate cross-talk between TβRI/II and the Shh pathway. We found that ceramide synthase 4 (CerS4)–generated ceramide stabilized the association between TβRI and the inhibitory factor Smad7, which limited the trafficking of TβRI/II to primary cilia. Expression of a mutant TβRI that signals but does not interact with Smad7 prevented the CerS4-mediated inhibition of migration in various cancer cells. Genetic deletion or knockdown of CerS4 prevented the formation of the Smad7-TβRI inhibitory complex and increased the association between TβRI and the transporter Arl6 through a previously unknown cilia-targeting signal (Ala 31 Thr 32 Ala 33 Leu 34 Gln 35 ) in TβRI. Mutating the cilia-targeting signal abolished the trafficking of TβRI to the primary cilia. Localization of TβRI to primary cilia activated a key mediator of Shh signaling, Smoothened (Smo), which stimulated cellular migration and invasion. TβRI-Smo cross-talk at the cilia in CerS4-deficient 4T1 mammary cancer cells induced liver metastasis from orthotopic allografts in both wild-type and CerS4-deficient mice, which was prevented by overexpression of Smad7 or knockdown of intraflagellar transport protein 88 (IFT88). Overall, these data reveal a ceramide-dependent mechanism that suppresses cell migration and invasion by restricting TβRI/II-Shh signaling selectively at the plasma membrane of the primary cilium. |
| Databáze: | OpenAIRE |
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