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- Title
c-Src-induced activation of ceramide metabolism impairs membrane microdomains and promotes malignant progression by facilitating the translocation of c-Src to focal adhesions.
- Authors
Kentaro KAJIWARA; Takayuki YAMADA; Takeshi BAMBA; Eiichiro FUKUSAKI; Fumio IMAMOTO; Masato OKADA; Chitose ONEYAMA
- Abstract
The proto-oncogenic tyrosine kinase c-Src is up-regulated in various human cancers, implicating its role in tumour 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. In the present study we show that c-Src up-regulation 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 (C-terminal Src kinase)- 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 FAK (focal adhesion kinase) and cortactin localized to focal adhesions/podosomes. In parallel with these events, anabolic metabolism of ceramides is activated by up-regulation of the de novo synthesis pathway. Inhibition of ceramide conversion into 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 tomalignant progression by promoting the translocation of c-Src to focal adhesions/podosomes.
- Subjects
CERAMIDES; METABOLISM; MEMBRANE microdomains; FOCAL adhesions; SPHINGOLIPIDS; TUMORS; BIOCHEMICAL research
- Publication
Biochemical Journal, 2014, Vol 458, Issue 1, p81
- ISSN
0264-6021
- Publication type
Article
- DOI
10.1042/BJ20130527