Phosphorylation of KIBRA by the extracellular signal-regulated kinase (ERK)-ribosomal S6 kinase (RSK) cascade modulates cell proliferation and migration

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• 作者：Shuping Yang ; Ming Ji ; Lin Zhang ; Yuanhong Chen ; Dirk Oliver Wennmann ; Joachim Kremerskothen ; Jixin Dong
• 关键词：ERK1/2 ; extracellular signal-regulated kinases 1/2 ; RSK1/2 ; p90 ribosomal S6 kinases 1/2 ; MAPK ; mitogen-activated protein kinases ; CDK1 ; cyclin-dependent kinase 1 ; WWC ; WW and C2 domain containing proteins
• 刊名：Cellular Signalling
• 出版年：February, 2014
• 年：2014
• 卷：26
• 期：2
• 页码：343-351
• 全文大小：1268 K

文摘

In mammals, KIBRA is defined as a memory performance-associated protein. The physiological function and regulation of KIBRA in non-neuronal cells are much less understood. Recent studies have identified KIBRA as a novel regulator of the Hippo signaling pathway, which plays a critical role in tumorigenesis by inhibiting cell proliferation and promoting apoptosis. We recently reported that KIBRA is phosphorylated by the mitotic kinases Aurora and cyclin-dependent kinase 1 during mitosis. In this current study, we show that KIBRA is also phosphorylated by the ERK (extracellular signal-regulated kinases)-RSK (p90 ribosomal S6 kinases) cascade. We demonstrated that ERK1/2 phosphorylate KIBRA at Ser⁵⁴⁸ in cells as well as in vitro. Moreover, we found that RSK1/2 specifically phosphorylates KIBRA at two highly conserved sites (Thr⁹²⁹ and Ser⁹⁴⁷) in vitro and in cells. RSK-mediated phosphorylation is required for KIBRA binding to RSK1, but not RSK2. Surprisingly, KIBRA knockdown impaired cell migration and proliferation in breast cancer cells. By using inducible-expression cell lines, we further show that phospho-regulation of KIBRA by ERK1/2 and RSK1/2 is required for proper cell proliferation and RSK-mediated phosphorylation also modulates KIBRA's migratory activity in MDA-MB-231 breast cancer cells. Our findings uncover unexpected results and a new mechanism through which KIBRA regulates cell migration and proliferation.