c-Src-induced activation of ceramide metabolism impairs membrane microdomains and promotes malignant progression by facilitating the translocation of c-Src to focal adhesions

The proto-oncogenic tyrosine kinase c-Src is upregulated in various human cancers, implicating its role in tumor progression. Upon activation, c-Src translocates to focal adhesions and initiates intracellular signalling cascades that promote malignant transformation, but the underlying mechanisms for c-Src translocation remain unclear. Here we show that c-Src upregulation perturbs sphingolipid/cholesterol enriched membrane microdomains by activating ceramide synthesis, resulting in promotion of c-Src translocation. Using an inducible c-Src expression system in Csk-deficient fibroblasts, we found that translocation of c-Src to focal adhesions/podosomes occurs in the later stages of cell transformation. Activated c-Src is liberated from microdomains and promotes the phosphorylation of focal adhesion kinase (FAK) and cortactin localised to focal adhesions/podosomes. In parallel with these events, anabolic metabolism of ceramides is activated by upregulation of the de novo synthesis pathway. Inhibition of ceramide conversion to glucosylceramide promotes liberation of c-Src from microdomains, and inhibition of de novo ceramide synthesis restores the microdomain distribution of c-Src and suppresses malignant phenotypes such as increased cell motility and anchorage-independent cell growth. These results suggest that c-Src-induced activation of ceramide synthesis impairs the integrity of microdomains and contributes to malignant progression by promoting the translocation of c-Src to ...
Source: BJ Signal - Category: Biochemistry Authors: Tags: BJ Signal Source Type: research