LIM protein JUB promotes epithelial–mesenchymal transition in colorectal cancer

Stauffer

Journal of Biological Chemistry

et al. 2016

Recent studies identified the adaptor protein Ajuba as a positive regulator of Yes-associated protein (YAP) oncogenic activity through inhibiting large tumor suppressor (Lats1/2) core kinases of the Hippo pathway, a signaling pathway that plays important roles in cancer. In this study, we define a novel mechanism for phospho-regulation of Ajuba in mitosis and its biological significance in cancer. We found that Ajuba is phosphorylated in vitro and in vivo by cyclin-dependent kinase 1 (CDK1) at Ser 119 and Ser 175 during the G2/M phase of the cell cycle. Mitotic phosphorylation of Ajuba controls the expression of multiple cell cycle regulators; however, it does not affect Hippo signaling activity, nor does it induce epithelial-mesenchymal transition. We further showed that mitotic phosphorylation of Ajuba is sufficient to promote cell proliferation and anchorage-independent growth in vitro and tumorigenesis in vivo. Collectively, our discoveries reveal a previously unrecognized mechanism for Ajuba regulation in mitosis and its role in tumorigenesis.

Section: Ajuba Phosphorylation Occurs During Normal Mitosis-tosupporting

confidence: 78%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Ajuba Phosphorylation by CDK1 Promotes Cell Proliferation and Tumorigenesis

Stauffer

Journal of Biological Chemistry

et al. 2016

Molecular and Cellular Biology

“…Furthermore, the LIM protein Ajuba (41,42), a known negative regulator of the Hippo pathway, via inhibition of LATS (large tumor suppressor kinase 1) kinase (43)(44)(45), that interacts with catenin family members at cell-cell contacts (adherens junctions) and with cadherin family members (46)(47)(48), has been found to promote the epithelial-to-mesenchymal transition in colorectal cancers (49), and its lentivirus transduction into malignant mesothelioma suppresses their proliferation via modulation of the Hippo pathway (50). In addition, findings demonstrating increased expression levels of YAP and survivin and decreased LATS activity in gastric and hepatocellular carcinomas (51,52) are consistent with Ajuba expression and localization possibly being an important regulator of the Hippo pathway in endothelia.…”

Section: Discussionmentioning

confidence: 99%

Adhesion Molecule-Mediated Hippo Pathway Modulates Hemangioendothelioma Cell Behavior

Madri

2014

Hemangioendotheliomas are categorized as intermediate-grade vascular tumors that are commonly localized in the lungs and livers. The regulation of this tumor cell's proliferative and apoptotic mechanisms is ill defined. We recently documented an important role for Hippo pathway signaling via endothelial cell adhesion molecules in brain microvascular endothelial cell proliferation and apoptosis. We found that endothelial cells lacking cell adhesion molecules escaped from contact inhibition and exhibited abnormal proliferation and apoptosis. Here we report on the roles of adherens junction molecule modulation of survivin and the Hippo pathway in the proliferation and apoptosis of a murine hemangioendothelioma (EOMA) cell. We demonstrated reduced adherens junction molecule (CD31 and VE-cadherin) expression, increased survivin and Ajuba expression, and a reduction in Hippo pathway signaling resulting in increased proliferation and decreased activation of effector caspase 3 in postconfluent EOMA cell cultures. Furthermore, we confirmed that YM155, an antisurvivin drug that interferes with Sp1-survivin promoter interactions, and survivin small interference RNA (siRNA) transfection elicited induction of VE-cadherin, decreased Ajuba expression, increased Hippo pathway and caspase activation and apoptosis, and decreased cell proliferation. These findings support the importance of the Hippo pathway in hemangioendothelioma cell proliferation and survival and YM155 as a potential therapeutic agent in this category of vascular tumors.

LIM protein Ajuba promotes liver cell proliferation through its involvement in DNA replication and DNA damage control

Stroka

2022

FEBS Letters

The LIM-domain protein Ajuba is associated with cell proliferation, a fundamental process of tissue regeneration and cancer. We report that in the liver, Ajuba expression is increased during regeneration and in tumour cells and tissues. Knockout of Ajuba using CRISPR/Cas9 is embryonic lethal in mice. shRNA targeting of Ajuba reduces cell proliferation, delays cell entry into Sphase, reduces cell survival and tumour growth in vivo and increases expression of the DNA damage marker γH2AX. Ajuba binding partners include proteins involved in DNA replication and damage, such as SKP2, MCM2, MCM7 and RPA70. Taken together, our data support that Ajuba promotes liver cell proliferation associated with development, regeneration and tumour growth and is involved in DNA replication and damage repair.