Article

Aurora-A phosphorylates, activates, and relocalizes the small GTPase RalA.

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Molecular and Cellular Biology (Impact Factor: 5.04). 11/2009; 30(2):508-23. DOI: 10.1128/MCB.00916-08
Source: PubMed

ABSTRACT The small GTPase Ras, which transmits extracellular signals to the cell, and the kinase Aurora-A, which promotes proper mitosis, can both be inappropriately activated in human tumors. Here, we show that Aurora-A in conjunction with oncogenic Ras enhances transformed cell growth. Furthermore, such transformation and in some cases also tumorigenesis depend upon S194 of RalA, a known Aurora-A phosphorylation site. Aurora-A promotes not only RalA activation but also translocation from the plasma membrane and activation of the effector protein RalBP1. Taken together, these data suggest that Aurora-A may converge upon oncogenic Ras signaling through RalA.

0 Bookmarks
 · 
147 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Since their discovery in 1986, Ral (Ras-like) GTPases have emerged as critical regulators of diverse cellular functions. Ral-selective guanine nucleotide exchange factors (RalGEFs) function as downstream effectors of the Ras oncoprotein, and the RalGEF-Ral signaling network comprises the third best characterized effector of Ras-dependent human oncogenesis. Because of this, Ral GTPases as well as their effectors are being explored as possible therapeutic targets in the treatment of RAS mutant cancer. The two Ral isoforms, RalA and RalB, interact with a variety of downstream effectors and have been found to play key and distinct roles in both normal and neoplastic cell physiology including regulation of vesicular trafficking, migration and invasion, tumor formation, metastasis, and gene expression. In this review we provide an overview of Ral biochemistry and biology, and we highlight recent discoveries.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 09/2014; · 5.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Molecular Cancer Therapeutics 11/2013; · 5.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: RLIP76 (Ral-interacting protein of 76 kDa) [also known as RalBP1 (Ral-binding protein 1)] is an effector for the Ral family small GTPases. RLIP76 has been implicated in a number of cell processes, including receptor-mediated endocytosis, cell migration, mitochondrial division and metabolite transport. RLIP76 has two recognizable domains in the centre of the protein sequence: a GAP (GTPase-activating protein) domain for the Rho family G-proteins and an RBD (Ral-binding domain). The remainder of RLIP76 has no discernable homology with other proteins. The RBD forms a simple coiled-coil of two α-helices, which interacts with RalB by binding to both of the nucleotide-sensitive 'switch' regions. Both of these RLIP76 helices are involved in the interaction with Ral, but the interhelix loop is left free. This is the location of one of the two ATP-binding sites that have been identified in RLIP76 and suggests that Ral interaction would not prevent ATP binding. The structure of the RhoGAP-RBD dyad shows that the two domains are fixed in their orientation by a relatively rigid linker. This domain arrangement allows the two domains to engage Rho family and Ral small G-proteins simultaneously at the membrane. This suggests that RLIP76 is a node for Rho and Ras family signalling.
    Biochemical Society Transactions 02/2014; 42(1):52-8. · 2.59 Impact Factor

Full-text (2 Sources)

Download
68 Downloads
Available from
May 27, 2014