Effect of IRS4 levels on PI 3-kinase signalling.

    Research output: Contribution to journalArticlepeer-review

    30 Citations (Scopus)

    Abstract

    Insulin receptor substrate 1 (IRS1) and IRS2 are well-characterized adapter proteins that relay signals from receptor tyrosine kinases to downstream components of signalling pathways. In contrast, the function of IRS4 is not well understood. IRS4 overexpression has been associated with acute lymphoblastic leukaemia and subungual exostosis, while point mutations of IRS4 have been found in melanomas. Here, we show that while IRS4 expression is low in most cancer cell lines, IRS4 mRNA and protein levels are markedly elevated in certain cells including the NCI-H720, DMS114, HEK293T and HEK293AAV lines. Surprisingly, IRS4 expression was also strongly induced when HEK293 cells were infected with retroviral particles and selected under puromycin, making IRS4 expression a potential off-target effect of retroviral expression vectors. Cells with high expression of IRS4 displayed high phosphatidylinositol (3,4,5)-trisphosphate (PIP3) levels, as well as elevated Akt and p70 S6 kinase activities, even in the absence of growth factors. PI 3-kinase (PI3K) signalling in these cells depends on IRS4, even though these cells also express IRS1/2. Knockdown of IRS4 also inhibited cell proliferation in cells with high levels of IRS4. Together, these findings suggest IRS4 as a potential therapeutic target for cancers with high expression of this protein.

    Original languageEnglish
    Pages (from-to)e73327
    Number of pages9
    JournalPLoS ONE
    Volume8
    Issue number9
    DOIs
    Publication statusPublished - 10 Sept 2013

    Fingerprint

    Dive into the research topics of 'Effect of IRS4 levels on PI 3-kinase signalling.'. Together they form a unique fingerprint.

    Cite this