Abstract
SummaryInsulin-induced AKT activation is dependent on phosphoinositide 3-kinase and opposed by tumor suppressor phosphatase and tensin homolog (PTEN). Our previous study demonstrates that myosin 1b (MYO1B) mediates arginase-II-induced activation of mechanistic target of rapamycin complex 1 that is regulated by AKT. However, the role of MYO1B in AKT activation is unknown. Here we show that silencing MYO1B in mouse embryonic fibroblasts (MEF) inhibits insulin-induced nuclear but not cytoplasmic AKT activation accompanied by elevated nuclear PTEN level. Co-immunoprecipitation, co-immunostaining, and proximity ligation assay show an interaction of MYO1B and PTEN resulting in reduced nuclear PTEN. Moreover, the elevated nuclear PTEN upon silencing MYO1B promotes apoptosis of MEFs and melanoma B16F10 cells. Taken together, we demonstrate that MYO1B, by interacting with PTEN, prevents nuclear localization of PTEN contributing to nuclear AKT activation and suppression of cell apoptosis. This may present a therapeutic approach for cancer treatment such as melanoma.
Highlights
AKT, known as protein kinase B (PKB), is a serine/threonine kinase that plays a crucial role in a variety of cellular processes including cell growth, proliferation, and metabolism (Mackenzie and Elliott, 2014; Nguyen et al, 2006)
By knocking down myosin 1b (MYO1B) in immortalized mouse embryonic fibroblasts (MEFs) and hepatocyte AML12 cells, we demonstrate that MYO1B, by interacting with phosphatase and tensin homolog (PTEN), prevents localization of PTEN in the nucleus, favoring nuclear AKT activation and cell survival in various cell types including melanoma cells
It is to be noted that silencing MYO1B in both cells did not influence the insulin-induced activation of MTORC1RPS6K1 pathway as monitored by ribosomal protein RPS6 phosphorylation at Ser240/244 (Figure S1), indicating that MYO1B is not required for insulin-induced MTORC1-RPS6K1 activation
Summary
AKT, known as protein kinase B (PKB), is a serine/threonine kinase that plays a crucial role in a variety of cellular processes including cell growth, proliferation, and metabolism (Mackenzie and Elliott, 2014; Nguyen et al, 2006). It has been reported that cytoplasmic AKT was able to translocate to the nucleus without phosphorylation as demonstrated in HEK293 cells, indicating that phosphorylation of AKT was not required for its nuclear localization (Saji et al, 2005). A study showed that long-term treatment of statins exhibited anticancer effects in A549 lung cancer cells, which is accompanied by a decline in nuclear AKT-Thr308 levels (Miraglia et al, 2012). All these studies suggest an important role of hyperactive nuclear AKT in carcinogenesis.
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