Identification of V23RalA-Ser194 as a Critical Mediator for Aurora-A-induced Cellular Motility and Transformation by Small Pool Expression Screening

Wu, Jiunn Chyi; Chen, Tzong Yueh; Yu, Chang Tze Ricky; Tsai, Si Jie; Hsu, Jung Mao; Tang, Ming Jer; Chou, Chen Kung; Lin, Wey Jinq; Yuan, Chiun Jye; Huang, Chi Ying F.

doi:10.1074/jbc.m411068200

Cited by 96 publications

(103 citation statements)

References 48 publications

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“…On the other hand, it is also possible that RalA itself may have a signaling role in cell separation. In correlation with our finding that active RalA localizes to the centrosome and the abscission site, Wu et al (35) reported that Aurora-A, a centrosome-localized kinase essential for cell cycle regulation, is able to activate RalA. In addition, RalBP1, a Ral effector containing a Rho GAP domain, was first identified as a centrosome antigen (36).…”

Section: Discussionsupporting

confidence: 62%

RalA-exocyst-dependent Recycling Endosome Trafficking Is Required for the Completion of Cytokinesis

Chen

Inoue

Hsu

et al. 2006

Journal of Biological Chemistry

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In eukaryotic cells, recycling endosome-mediated trafficking contributes to the completion of cytokinesis, in a manner under the control of the centrosome. We report that the exocyst complex and its interacting GTPase RalA play a critical role in this polarized trafficking process. RalA resides in the recycling endosome and relocates from the pericentrosomal region to key cytokinetic structures including the cleavage furrow, and later, the abscission site. This event is coupled to the dynamic redistribution of the exocyst proteins. These associate with the centrosome in interphase and concentrate on the central spindle/ midbody during cytokinesis. Disruption of RalA-exocyst function leads to cytokinesis failure in late stages, particularly abscission, resembling the cytokinesis defects induced by loss of centrosome function. These data suggest that RalA and the exocyst may regulate vesicle delivery to the centrosome-related abscission site during the terminal stage of cytokinesis, implicating RalA as a critical regulator of cell cycle progression.

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Section: Discussionsupporting

confidence: 62%

RalA-exocyst-dependent Recycling Endosome Trafficking Is Required for the Completion of Cytokinesis

Chen

Inoue

Hsu

et al. 2006

Journal of Biological Chemistry

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“…Aurora-A enhances collagen I -induced cell migration and anchorage-independent growth in Aurora-A -stable cell line by activating RalA (104). In the case of Aurora-B, overexpression or nondegradation mutants could promote anchorage-independent growth in soft agar (23).…”

Section: Aurora Kinases In Other Signaling Pathways and Tumorigenesismentioning

confidence: 99%

“…Furthermore, both Aurora-A and Aurora-B promote inappropriate cellular mobility (23,104), which underlies invasion and metastasis of tumor cells (105). Aurora-A enhances collagen I -induced cell migration and anchorage-independent growth in Aurora-A -stable cell line by activating RalA (104).…”

Section: Aurora Kinases In Other Signaling Pathways and Tumorigenesismentioning

confidence: 99%

Roles of Aurora Kinases in Mitosis and Tumorigenesis

Bian

Jiang

et al. 2007

Molecular Cancer Research

539

504

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Aurora kinases, which have been implicated in several vital events in mitosis, represent a protein kinase family highly conserved during evolution. The activity of Aurora kinases is delicately regulated, mainly by phosphorylation and degradation. Deregulation of Aurora kinase activity can result in mitotic abnormality and genetic instability, leading to defects in centrosome function, spindle assembly, chromosome alignment, and cytokinesis. Both the expression level and the kinase activity of Aurora kinases are found to be up-regulated in many human cancers, indicating that these kinases might serve as useful targets for the development of anticancer drugs. This review focuses on recent progress on the roles of Aurora kinases in mitosis and tumorigenesis. (

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“…The recent characterization of RalA S194 as a substrate for AAK (9, 10) and our finding that RalA S194 phosphorylation levels correlated with Aurora A activation, as indicated by T288 phosphorylation, prompted us to investigate whether MLN8237 could be an effective anti-RalA therapy for pancreatic cancer. Most cell lines were largely insensitive to MLN8237 using the MTT assay to assess anchorage-dependent growth.…”

Section: Discussionmentioning

confidence: 99%

“…Hahn and colleagues showed that serine-threonine protein phosphatase 2A dephosphorylation of RalA at S183 and S194 abolished RalA transforming activity (8). Two other studies determined that S194 could be phosphorylated by Aurora A and that this phosphorylation was essential for RalA transforming activity (9) and RalA-dependent PDAC anchorage-independent and tumorigenic growth (10). Aurora A phosphorylation alters RalA subcellular localization and interaction with effectors (10, 11).…”

Section: Introductionmentioning

confidence: 99%

Response to MLN8237 in Pancreatic Cancer Is Not Dependent on RalA Phosphorylation

Neel

Stratford

Shinde

et al. 2014

Molecular Cancer Therapeutics

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The high prevalence of KRAS mutations and importance of the RalGEF-Ral pathway downstream of activated K-Ras in pancreatic ductal adenocarcinoma (PDAC) emphasize the importance of identifying novel methods by which to therapeutically target these pathways. It was recently demonstrated that phosphorylation of RalA S194 by Aurora A kinase is critical for PDAC tumorigenesis. We sought to evaluate the Aurora A kinase-selective inhibitor MLN8237 as a potential indirect anti-RalA targeted therapy for PDAC. We utilized a site-specific phospho-S194 RalA antibody and determined that RalA S194 phosphorylation levels were elevated in a subset of PDAC cell lines and human tumors relative to unmatched normal controls. Effects of MLN8237 on anchorage-independent growth in PDAC cell lines and growth of patient-derived xenografts (PDX) were variable, with a subset of cell lines and PDX showing sensitivity. Surprisingly, RalA S194 phosphorylation levels in PDAC cell lines or PDX tumors did not correlate with MLN8237 responsiveness. However, we identified Ki67 as a possible early predictive biomarker for response to MLN8237 in PDAC. These results indicate that MLN8237 treatment may be effective for a subset of PDAC patients independent of RalA S194 phosphorylation. Ki67 may be an effective pharmacodynamic biomarker to identify response early in the course of treatment.

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Identification of V23RalA-Ser194 as a Critical Mediator for Aurora-A-induced Cellular Motility and Transformation by Small Pool Expression Screening

Cited by 96 publications

References 48 publications

RalA-exocyst-dependent Recycling Endosome Trafficking Is Required for the Completion of Cytokinesis

RalA-exocyst-dependent Recycling Endosome Trafficking Is Required for the Completion of Cytokinesis

Roles of Aurora Kinases in Mitosis and Tumorigenesis

Response to MLN8237 in Pancreatic Cancer Is Not Dependent on RalA Phosphorylation

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