Aurora-A Phosphorylates, Activates, and Relocalizes the Small GTPase RalA

Lim, Kian-Huat; Brady, Donita C.; Kashatus, David F.; Ancrile, Brooke B.; Der, Channing J.; Cox, Adrienne D.; Counter, Christopher M.

doi:10.1128/mcb.00916-08

Cited by 102 publications

(143 citation statements)

References 64 publications

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“…RalA S194 phosphorylation by AAK can alter subcellular localization (10). We investigated whether MLN8237 treatment altered the intracellular localization of RalA in four PDAC cells lines; three with low (HuPT3, CFPAC-1, and Panc10.05) and one with high (HPAC) IC50 values in anchorage-independent growth assays.…”

Section: Resultsmentioning

confidence: 99%

“…Studies demonstrated the importance of RalA and, more specifically, phosphorylation at S194 by AAK, in tumor development (6, 7, 10). The importance of RalA S194 phosphorylation in tumorigenesis makes AAK an attractive druggable target downstream of oncogenic Ras activation.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…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). Activation of Aurora A promotes mitochondrial localization of RalA and promotes mitochondrial fission (11), which may present a mechanism for Aurora A contribution to tumorigenesis (12).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Membrane extraction by calmodulin underpins the disparate signalling of RalA and RalB

2022

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Both RalA and RalB interact with the ubiquitous calcium sensor, calmodulin (CaM). New structural and biophysical characterisation of these interactions strongly suggests that, in the native membrane‐associated state, only RalA can be extracted from the membrane by CaM and this non‐canonical interaction could underpin the divergent signalling roles of these closely related GTPases. The isoform specificity for RalA exhibited by CaM is hypothesised to contribute to the disparate signalling roles of RalA and RalB in mitochondrial dynamics. This would lead to CaM shuttling RalA to the mitochondrial membrane but leaving RalB localisation unperturbed, and in doing so triggering mitochondrial fission pathways rather than mitophagy.

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Ral signaling pathway in health and cancer

et al. 2017

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The Ral (Ras‐Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors.

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Aurora-A Phosphorylates, Activates, and Relocalizes the Small GTPase RalA

Cited by 102 publications

References 64 publications

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

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

Membrane extraction by calmodulin underpins the disparate signalling of RalA and RalB

Ral signaling pathway in health and cancer

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