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

Kentaro Kajiwara, Takayuki Yamada, Takeshi Bamba, Eiichiro Fukusaki, Fumio Imamoto, Masato Okada, Chitose Oneyama

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10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)81-93
Number of pages13
JournalBiochemical Journal
Volume458
Issue number1
DOIs
Publication statusPublished - Jan 15 2014
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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