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Regulation of TGF‐Beta Receptor Signaling and Cell Migration by Ceramide Metabolism

Recent studies indicate that ceramide species play diverse biological functions including, skin barrier function, liver homeostasis, cell death and cancer pathogenesis, highlighting the importance of ceramide synthases (CerS) in these processes. Migration, a part of these processes, also is effected by ceramide metabolism. However, the molecular mechanism of CerS/ceramide involved is unknown. Here, we investigated the effect of CerS on migration and its related signal pathways in situ and in vivo model. Interestingly, our data show that among CerS only CerS4 is related to cell migration. Here, we also have generated CerS4‐/‐ mice, and these mice were viable with no lethal tissue. Interestingly, we observed that loss of CerS4 resulted in irreversible alopecia, which was associated with hyper‐proliferation and migration of keratinocytes. Mechanistically, we show that knockout/knockdown of CerS4 enhances cell migration by which ligand‐independent signaling of TGFβ receptors RI and RII in various cell types, including keratinocytes, MEFs, and cancer cells. Additionally, low level of TGFβR1‐Smad7 interaction was found in knockdown of CerS4 cells. Moreover, we found that ceramide interact with Smad7 and interaction was decreased by knockdown of CerS4. Thus, ceramide‐Smad7 binding modulates plasma membrane association of TGFβR1, and inhibits its signaling through Sonic‐Hedgehog (Shh) signaling for migration. In fact, inhibition of TGFβR/Shh signaling using molecular or pharmacologic inhibitors almost completely prevented cell migration in response to CerS4 knockdown. These data suggest that CerS4/ceramide signaling plays key roles in the regulation of cell migration via controlling the TGFβR/Shh axis.