TGF-? receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis.

ABSTRACT: Signaling by the transforming growth factor-? (TGF-?) receptors I and II (T?RI/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 T?RI/II trafficking to primary cilia to attenuate cross-talk between T?RI/II and the Shh pathway. We found that ceramide synthase 4 (CerS4)-generated ceramide stabilized the association between T?RI and the inhibitory factor Smad7, which limited the trafficking of T?RI/II to primary cilia. Expression of a mutant T?RI 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-T?RI inhibitory complex and increased the association between T?RI and the transporter Arl6 through a previously unknown cilia-targeting signal (Ala31Thr32Ala33Leu34Gln35) in T?RI. Mutating the cilia-targeting signal abolished the trafficking of T?RI to the primary cilia. Localization of T?RI to primary cilia activated a key mediator of Shh signaling, Smoothened (Smo), which stimulated cellular migration and invasion. T?RI-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 T?RI/II-Shh signaling selectively at the plasma membrane of the primary cilium.

SUBMITTER: Gencer S 

PROVIDER: S-EPMC5818989 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature