A Requirement for ZAK Kinase Activity in Canonical TGF-β Signaling

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• 作者：Shyam Nyati^* ; ^&dagger ; ; ^{shyamnya@med.umich.edu} ; Areeb Chator^* ; Katerina Schinske^* ; Brandon S Gregg^* ; Brian Dale Ross^&Dagger ; ; Alnawaz Rehemtulla^* ; ^&dagger ; ; ^&Dagger ; ; ^{alnawaz@med.umich.edu}
• 刊名：Translational Oncology
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：9
• 期：6
• 页码：473-481
• 全文大小：1501 K
• 卷排序：9

文摘

The sterile alpha motif and leucine zipper containing kinase ZAK (AZK, MLT, MLK7), is a MAPK-kinase kinase (MKKK). Like most MAPKKKs which are known to activate the c-Jun. amino-terminal kinase (JNK) pathway, ZAK has been shown to participate in the transduction of Transforming growth factor-β (TGF-β)-mediated non-canonical signaling. A role for ZAK in SMAD-dependent, canonical TGF-β signaling has not been previously appreciated. Using a combination of functional genomics and biochemical techniques, we demonstrate that ZAK regulates canonical TGFβRI/II signaling in lung and breast cancer cell lines and may serve as a key node in the regulation of TGFBR kinase activity. Remarkably, we demonstrate that siRNA mediated depletion of ZAK strongly inhibited TGF-β dependent SMAD2/3 activation and subsequent promoter activation (SMAD binding element driven luciferase expression; SBE4-Luc). A ZAK specific inhibitor (DHP-2), dose-dependently activated the bioluminescent TGFBR-kinase activity reporter (BTR), blocked TGF-β induced SMAD2/3 phosphorylation and SBE4-Luc activation and cancer cell-invasion. In aggregate, these findings identify a novel role for the ZAK kinase in canonical TGF-β signaling and an invasive cancer cell phenotype thus providing a novel target for TGF-β inhibition.