A novel 4.1 ezrin radixin moesin (FERM)‐containing protein, ‘Willin’

Gunn‐Moore, Frank; Welsh, Gavin I.; Herron, Lissa R.; Brannigan, Frances; Kanamarlapudi, Venkateswarlu; Gillespie, Stewart; Brandwein-Gensler, Margaret; Madan, Rashna; Tavaré, Jeremy M.; Brophy, Peter; Prystowsky, Michael B.; Guild, Simon

doi:10.1016/j.febslet.2005.07.097

Cited by 39 publications

(64 citation statements)

References 20 publications

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“…Although hEx is the closest human homolog to ex, their structure is considerably different. hEx and Drosophila ex share the conserved FERM domain, but hEx lacks the C-terminal region of Drosophila ex which contains several PPXY motifs responsible for hEx functions as a tumor suppressor in human cancer cell lines S Visser-Grieve et al protein-protein interactions (Gunn-Moore et al, 2005;Badouel et al, 2009). Interestingly, it has been suggested that the tumor suppressor function of Drosophila ex is mediated primarily via its C-terminus (Pellock et al, 2007), which is further evidence that hEx and Drosophila ex, although both tumor suppressors, mediate their effects by distinct mechanisms.…”

Section: Resultsmentioning

confidence: 99%

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Human homolog of Drosophila expanded, hEx, functions as a putative tumor suppressor in human cancer cell lines independently of the Hippo pathway

2011

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The Hippo signaling network is proving to be an essential regulator within the cell, participating in multiple cellular phenotypes including cell proliferation, apoptosis, cell migration and organ size control. Much of this pathway is conserved from flies to mammals; however, how the upstream components, namely Expanded, affect downstream processes in mammalian systems has remained elusive. Only recently has human Expanded (hEx), also known as FRMD6 or Willin, been identified. However, its functional significance with respect to its putative tumor suppressor function and activation of the Hippo pathway has not been studied. In this study, we show for the first time that hEx possesses several tumor suppressor properties. First, hEx dramatically inhibits cell proliferation in two human cancer cell lines, MDA-MB-231 and MDA-MB-436 cells, and sensitizes these cells to the chemotherapeutic drug Taxol. Furthermore, downregulation of hEx in the immortalized MCF10A breast cell line leads to enhanced proliferation and resistance to Taxol treatment. As evidence for its tumor suppressor function, overexpression of hEx inhibits colony formation, soft agar colony growth in vitro and in vivo tumor growth in nude mice. Although Drosophila expanded (ex) can activate the Hippo pathway, surprisingly no significant alterations were discovered in the phosphorylation status of any of the Hippo pathway components, including downstream tumor suppressor LATS1, upon overexpression of hEx. In addition, knockdown of both LATS1 and LATS2 in hEx-overexpressing cells was unable to rescue the hEx phenotype, suggesting that hEx functions independently of the Hippo pathway in this cell line. Alternatively, we propose a mechanism through which hEx inhibits progression through the S phase of the cell cycle by upregulating p21Cip1 and downregulating Cyclin A. This is the first study to functionally characterize hEx and show that hEx acts in a distinct manner compared with Drosophila expanded.

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Section: Resultsmentioning

confidence: 99%

“…hEx is a FERM domain protein similar to Merlin and the ERM (Ezrin, Radixin, Moesin) family of cytoskeletal crosslinkers and is localized throughout the cytoplasm or along the plasma membrane (Gunn-Moore et al, 2005). In this study, we outline the key cellular functions of hEx and suggest that hEx possesses tumor suppressor properties.…”

Section: Introductionmentioning

confidence: 99%

Human homolog of Drosophila expanded, hEx, functions as a putative tumor suppressor in human cancer cell lines independently of the Hippo pathway

2011

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“…Interestingly, membrane skeleton proteins such as b-spectrin and filamin, as well as myosin IIA and moesin, were identified in a screen of proteins able to interact with PI3P. 34,35 Conversely, vinculin that localizes to the membrane skeleton is normal in PI3K-C2a WT/D1268A platelets and was found not to bind PI3P. 36 Thus, loss of a PI3K-C2a-derived pool of PI3P with low turnover may induce a mislocalization/ stabilization of proteins at the membrane skeleton, leading to modifications in membrane biophysical properties.…”

Section: Discussionmentioning

confidence: 99%

Essential role of class II PI3K-C2α in platelet membrane morphology

Valet

Chicanne

Severac

et al. 2015

Blood

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Key Points• PI3K-C2a controls platelet membrane structure and remodeling.• PI3K-C2a is a key regulator of a basal housekeeping PI3P pool in platelets.The physiologic roles of the class II phosphoinositide 3-kinases (PI3Ks) and their contributions to phosphatidylinositol 3-monophosphate (PI3P) and PI(3,4)P 2 production remain elusive. Here we report that mice heterozygous for a constitutively kinase-dead PI3K-C2a display aberrant platelet morphology with an elevated number of barbell-shaped proplatelets, a recently discovered intermediate stage in the final process of platelet production. Platelets with heterozygous PI3K-C2a inactivation have critical defects in a-granules and membrane structure that are associated with modifications in megakaryocytes. These platelets are more rigid and unable to form filopodia after stimulation. Heterozygous PI3K-C2a inactivation in platelets led to a significant reduction in the basal pool of PI3P and a mislocalization of several membrane skeleton proteins known to control the interactions between the plasma membrane and cytoskeleton. These alterations had repercussions on the performance of platelet responses with delay in the time of arterial occlusion in an in vivo model of thrombosis and defect in thrombus formation in an ex vivo blood flow system. These data uncover a key role for PI3K-C2a activity in the generation of a basal housekeeping PI3P pool and in the control of membrane remodeling, critical for megakaryocytopoiesis and normal platelet production and function. (Blood. 2015;126(9):1128-1137

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“…To make the retroviral or GFP-tagged Ajuba expression constructs, the above full-length cDNA was cloned into the MaRX TM IV (45) or pEGFP-C1 vector (Clontech), respectively. HA-FRMD6 (HA-EX) was made by cloning FRMD6 cDNA (46) into the pcDNA3.1-HA vector (45). Myc-Lats2 has been described (45).…”

Section: Methodsmentioning

confidence: 99%

Ajuba Phosphorylation by CDK1 Promotes Cell Proliferation and Tumorigenesis

Chen

Stauffer

Chen

et al. 2016

Journal of Biological Chemistry

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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.

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A novel 4.1 ezrin radixin moesin (FERM)‐containing protein, ‘Willin’

Cited by 39 publications

References 20 publications

Human homolog of Drosophila expanded, hEx, functions as a putative tumor suppressor in human cancer cell lines independently of the Hippo pathway

Human homolog of Drosophila expanded, hEx, functions as a putative tumor suppressor in human cancer cell lines independently of the Hippo pathway

Essential role of class II PI3K-C2α in platelet membrane morphology

Ajuba Phosphorylation by CDK1 Promotes Cell Proliferation and Tumorigenesis

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