The RalGEF-Ral Effector Signaling Network: The Road Less Traveled for Anti-Ras Drug Discovery

Neel, Nicole F.; Martin, Timothy D.; Stratford, Jeran K.; Zand, Tanya P.; Reiner, David J.; Der, Channing J.

doi:10.1177/1947601911407329

Cited by 106 publications

(116 citation statements)

References 139 publications

(154 reference statements)

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“…It has been shown that oncogenic Ras activates RalGEFs, which in turn activate the Ras-like small GTPases RalA and RalB (Lim et al, 2005;Urano et al, 1996;White et al, 1996;Wolthuis et al, 1998). Moreover, RalGEF-Ral signaling stimulates gene expression (Neel et al, 2011). It is therefore likely that Ral mediates the observed increased levels of exocyst proteins in Ras V12 cells.…”

Section: Oncogenic Ras Stimulates Eiger/tnf Exocytosismentioning

confidence: 91%

“…Indeed, the fact that blocking exocytosis of Eiger/TNF can suppress oncogenic Ras-mediated growth highlights the importance of Eiger/TNF exocytosis in cancer biology. Exocytosis proteins are conserved and have been implicated in diverse human cancers types, including Ras cancers (Cheng et al 2004(Cheng et al , 2005Issaq et al, 2010;Neel et al, 2011;Palmer et al, 2002), suggesting that a similar tumor-promoting mechanism could be at play in vertebrates. Because sec15 null mutation does not cause cell lethality and the gene is evolutionarily conserved, it suggests a new type of potential therapeutic targets.…”

Section: Oncogenic Ras Stimulates Eiger/tnf Exocytosismentioning

confidence: 99%

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Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth

Chabu

2014

Development

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Oncogenic mutations in Ras deregulate cell death and proliferation to cause cancer in a significant number of patients. Although normal Ras signaling during development has been well elucidated in multiple organisms, it is less clear how oncogenic Ras exerts its effects. Furthermore, cancers with oncogenic Ras mutations are aggressive and generally resistant to targeted therapies or chemotherapy. We identified the exocytosis component Sec15 as a synthetic suppressor of oncogenic Ras in an in vivo Drosophila mosaic screen. We found that oncogenic Ras elevates exocytosis and promotes the export of the pro-apoptotic ligand Eiger (Drosophila TNF). This blocks tumor cell death and stimulates overgrowth by activating the JNK-JAK-STAT non-autonomous proliferation signal from the neighboring wild-type cells. Inhibition of Eiger/TNF exocytosis or interfering with the JNK-JAK-STAT non-autonomous proliferation signaling at various steps suppresses oncogenic Rasmediated overgrowth. Our findings highlight important cell-intrinsic and cell-extrinsic roles of exocytosis during oncogenic growth and provide a new class of synthetic suppressors for targeted therapy approaches.

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Section: Oncogenic Ras Stimulates Eiger/tnf Exocytosismentioning

confidence: 91%

Section: Oncogenic Ras Stimulates Eiger/tnf Exocytosismentioning

confidence: 99%

Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth

Chabu

2014

Development

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“…A second important group of effectors is the class IA catalytic subunits of phosphoinositide 3-kinases (PI3Ks). The third-best validated class of effectors required for Ras-mediated oncogenesis is comprised of guanine nucleotide exchange factors (RalGEFs) for the highly related RalA and RalB small GTPases (7,51). In PDAC, our studies suggest that the RalGEF-Ral effector pathway may be more essential than Raf or PI3K signaling for mutant KRAS-dependent tumor growth (34).…”

mentioning

confidence: 89%

The RalB Small GTPase Mediates Formation of Invadopodia through a GTPase-Activating Protein-Independent Function of the RalBP1/RLIP76 Effector

Neel

Rossman

Martin

et al. 2012

Molecular and Cellular Biology

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Our recent studies implicated key and distinct roles for the highly related RalA and RalB small GTPases (82% sequence identity) in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and invasive and metastatic growth, respectively. How RalB may promote PDAC invasion and metastasis has not been determined. In light of known Ral effector functions in regulation of actin organization and secretion, we addressed a possible role for RalB in formation of invadopodia, actin-rich membrane protrusions that contribute to tissue invasion and matrix remodeling. We determined that a majority of KRAS mutant PDAC cell lines exhibited invadopodia and that expression of activated K-Ras is both necessary and sufficient for invadopodium formation. Invadopodium formation was not dependent on the canonical Raf-MEK-ERK effector pathway and was instead dependent on the Ral effector pathway. However, this process was more dependent on RalB than on RalA. Surprisingly, RalB-mediated invadopodium formation was dependent on RalBP1/RLIP76 but not Sec5 and Exo84 exocyst effector function. Unexpectedly, the requirement for RalBP1 was independent of its best known function as a GTPase-activating protein for Rho small GTPases. Instead, disruption of the ATPase function of RalBP1 impaired invadopodium formation. Our results identify a novel RalB-mediated biochemical and signaling mechanism for invadopodium formation.T he ability of cancer cells to degrade the extracellular matrix and invade through the basement membrane is essential for metastatic disease (23, 53). Pancreatic cancer is a highly aggressive and invasive disease, though the mechanisms by which pancreatic ductal adenocarcinoma (PDAC) cells mediate invasion and metastasis are largely unknown (65). Mutational activation of K-Ras is an early initiating event that occurs in essentially 100% of human pancreatic tumors (28). However, K-Ras activity may also contribute to invasion and metastasis of PDAC (12), suggesting that K-Ras plays a role in multiple steps of tumor progression.The formation of dynamic, actin-rich, extracellular matrix-degrading protrusions known as invadopodia is linked to the invasive phenotype of cancer cells (10,11,21,66). Invadopodia have been identified in multiple malignancies, including melanoma, glioblastoma, breast, and head and neck squamous cell carcinoma, and whether they are seen in PDAC has not been determined. While members of the Rho family of small GTPases (Rac1, RhoA, and Cdc42) have been implicated in invadopodium formation (19, 37, 52), whether aberrant Ras activation can promote invadopodium formation has not been addressed.KRAS encodes a small GTPase that serves as a signaling node activating multiple downstream pathways in response to extracellular stimuli (18, 31). Activating mutations in KRAS encode a constitutively activated K-Ras protein which stimulates persistent, deregulated activation of downstream signaling pathways. The canonical effectors of Ras are the Raf serine/threonine kinases, which phosphorylate and activate the MEK1 and MEK...

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“…There is increasing evidence for the importance of the RalA and RalB small GTPases in mutant Ras-driven oncogenesis (4, 5). RNAi knockdown of endogenous RalA in PDAC cells significantly impaired anchorage-independent growth whereas knockdown of RalB impaired Matrigel invasion in vitro and experimental metastasis in vivo (6).…”

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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The RalGEF-Ral Effector Signaling Network: The Road Less Traveled for Anti-Ras Drug Discovery

Cited by 106 publications

References 139 publications

Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth

Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth

The RalB Small GTPase Mediates Formation of Invadopodia through a GTPase-Activating Protein-Independent Function of the RalBP1/RLIP76 Effector

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

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