Activation of RalA is critical for Ras-induced tumorigenesis of human cells

Lim, Kian-Huat; Baínes, Andrew D.; Fiordalisi, James J.; Shipitsin, Michail; Feig, Larry A.; Cox, Adrienne D.; Der, Channing J.; Counter, Christopher M.

doi:10.1016/j.ccr.2005.04.030

Cited by 324 publications

(355 citation statements)

References 55 publications

(37 reference statements)

Supporting

Mentioning

338

Contrasting

Order By: Relevance

“…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%

“…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). Importantly, RalA-GTP and RalB-GTP levels were significantly higher in PDAC cell lines and in patient tumors relative to normal matched and unmatched samples (6, 7). Taken together, these studies suggest that therapeutic inhibition of Ral may be an effective therapy for KRAS mutant PDAC.…”

Section: Introductionmentioning

confidence: 93%

See 1 more Smart Citation

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

Neel

Stratford

Shinde

et al. 2014

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

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

Neel

Stratford

Shinde

et al. 2014

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, in bladder and prostate cancer cells, RalB stimulates migration, whereas RalA is antimigratory (Oxford et al, 2005). In a defined model of Ras-driven tumorigenesis of human cells, RalA has been shown to promote transformation and tumor formation, while RalB has been shown to inhibit both (Lim et al, 2005). RalB depletion was also shown to trigger apoptosis in certain cancer cell lines, and this was reversed by simultaneous depletion of RalA and RalB (Chien and White, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Although studies on rodent tumorigenesis suggested that RalGEFs, and by extension RalA and RalB, are not particularly tumorigenic (White et al, 1995), recent results indicate more important roles for RalA and RalB in human cancer. For example, RalGEFs have been shown to be the most important effectors downstream of Ras in the transformation of human cells (Hamad et al, 2002) and RalA is a necessary component of Rasdriven tumorigenesis (Lim et al, 2005). Conversely, RalB has been shown to be pro-migratory in human bladder and prostate cancer cells (Oxford et al, 2005), and depletion of RalB via short interfering RNA (siRNA) has been shown to trigger apoptosis in many human cancer cell lines (Chien and White, 2003).…”

Section: Introductionmentioning

confidence: 99%

Expression profiling of Ral-depleted bladder cancer cells identifies RREB-1 as a novel transcriptional Ral effector

2007

View full text Add to dashboard Cite

Although the monomeric GTPases RalA and RalB have been shown to regulate a variety of transcription factors, little is known regarding the differences or similarities in transcriptional programs regulated by RalA compared to RalB. Further, the association of these transcriptional pathways to human carcinogenesis and progression remains unclear. Here, we studied the role of RalA and/ or RalB in transcriptional regulation by combining short interfering RNA depletion of Ral with gene expression profiling via microarray in the human bladder cancer cell line, UMUC-3. A large number of genes were found to be similarly modulated in cells with RalA and RalB depletion, suggesting that RalA and RalB impinge on overlapping transcriptional signaling pathways. However, smaller sets of genes were modulated by depletion of RalA or RalB, indicating that these closely related proteins also regulate nonoverlapping transcriptional pathways. Computational analysis of upstream sequences of genes modulated by Ral depletion identified Ras-responsive element-binding protein (RREB)-1, as a putative Ral transcriptional target, which we verified experimentally. Importantly, as a group, Ral-regulated probe sets identified here were disproportionally represented among those differentially expressed as a function of human bladder transformation. Taken together, these data strongly suggest that Ral family members mediate both common and specific transcriptional programs that are associated with human cancer and identify RREB-1 as a novel transcriptional effector of Ral.

show abstract

“…Ral proteins (RalA and RalB) are members of the small GTPase Ras superfamily (Chardin and Tavitian, 1986) and play an essential role in a variety of physiological and pathological processes in mammalian cells, including exocytosis (Moskalenko et al, 2002;Cascone et al, 2008), cell proliferation (Chien and White, 2003;Lim et al, 2005), and oncogenic transformation (Rangarajan et al, 2004). As with other members of the Ras family, Ral cycles between its activated GTP-bound form and inactivated GDP-bound form in the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

Structural study of the Cdc25 domain from Ral-specific guanine-nucleotide exchange factor RalGPS1a

Peng

Guan

et al. 2011

Protein Cell

View full text Add to dashboard Cite

The guanine-nucleotide exchange factor (GEF) RalGPS1a activates small GTPase Ral proteins such as RalA and RalB by stimulating the exchange of Ral bound GDP to GTP, thus regulating various downstream cellular processes. RalGPS1a is composed of an Nterminal Cdc25-like catalytic domain, followed by a PXXP motif and a C-terminal pleckstrin homology (PH) domain. The Cdc25 domain of RalGPS1a, which shares about 30% sequence identity with other Cdc25-domain proteins, is thought to be directly engaged in binding and activating the substrate Ral protein. Here we report the crystal structure of the Cdc25 domain of RalGPS1a. The bowl shaped structure is homologous to the Cdc25 domains of SOS and RasGRF1. The most remarkable difference between these three Cdc25 domains lies in their active sites, referred to as the helical hairpin region. Consistent with previous enzymological studies, the helical hairpin of RalGPS1a adopts a conformation favorable for substrate binding. A modeled RalGPS1a-RalA complex structure reveals an extensive binding surface similar to that of the SOS-Ras complex. However, analysis of the electrostatic surface potential suggests an interaction mode between the RalGPS1a active site helical hairpin and the switch 1 region of substrate RalA distinct from that of the SOS-Ras complex.

show abstract

Activation of RalA is critical for Ras-induced tumorigenesis of human cells

Cited by 324 publications

References 55 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

Expression profiling of Ral-depleted bladder cancer cells identifies RREB-1 as a novel transcriptional Ral effector

Structural study of the Cdc25 domain from Ral-specific guanine-nucleotide exchange factor RalGPS1a

Contact Info

Product

Resources

About