RalA and RalB differentially regulate development of epithelial tight junctions

Hazelett, C. Clayton; Sheff, David; Yeaman, Charles

doi:10.1091/mbc.e11-07-0657

Cited by 33 publications

(46 citation statements)

References 51 publications

(75 reference statements)

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“…In metazoans, Ral GTPases (RalA and RalB) interact with both Sec5 and Exo84, and these interactions have been implicated in many processes, including cell migration, autophagy, neurogenesis and cancer (Brymora et al, 2001;Sugihara et al, 2002;Moskalenko et al, 2002Moskalenko et al, , 2003Polzin et al, 2002;Balakireva et al, 2006;Bodemann et al, 2011;Chen et al, 2006Chen et al, , 2007Chien et al, 2006;Hazelett et al, 2011;Lalli, 2009;Rosse et al, 2006). Cell fractionation studies have shown that Sec5 and Exo84 are in separate sub-complexes (Moskalenko et al, 2003), and structure analysis has demonstrated that Sec5 and Exo84 competitively bind to GTP-Ral (Jin et al, 2005).…”

Section: Ralmentioning

confidence: 99%

The Exocyst at a Glance

Guo

2015

Journal of Cell Science

222

250

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The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. Spatial and temporal control of exocytosis through the exocyst has a crucial role in a number of physiological processes, such as morphogenesis, cell cycle progression, primary ciliogenesis, cell migration and tumor invasion. In this Cell Science at a Glance poster article, we summarize recent works on the molecular organization, function and regulation of the exocyst complex, as they provide rationales to the involvement of this complex in such a diverse array of cellular processes.

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Section: Ralmentioning

confidence: 99%

The Exocyst at a Glance

Guo

2015

Journal of Cell Science

222

250

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“…This regulation of vesicular trafficking controls various complex cellular functions such as polarized membrane formation, cytokinesis, tight junction formation, and tumor cell invasion [41][42][43][44] . RALB also interacts with Sec5 to activate the IκB kinase TBK1 [21,45] .…”

Section: Ras Mutation and Cancer Therapeuticsmentioning

confidence: 99%

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

Guin

Theodorescu

2015

Acta Pharmacol Sin

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Activating RAS mutations are common in human tumors. These mutations are often markers for resistance to therapy and subsequent poor prognosis. So far, targeting the RAF-MEK-ERK and PI3K-AKT signaling pathways downstream of RAS is the only promising approach in the treatment of cancer patients harboring RAS mutations. RAL GTPase, another downstream effector of RAS, is also considered as a therapeutic option for the treatment of RAS-mutant cancers. The RAL GTPase family comprises RALA and RALB, which can have either divergent or similar functions in different tumor models. Recent studies on non-small cell lung cancer (NSCLC) have showed that different RAS mutations selectively activate specific effector pathways. This observation requires broader validation in other tumor tissue types, but if true, will provide a new approach to the treatment of RAS-mutant cancer patients by targeting specific downstream RAS effectors according to the type of RAS mutation. It also suggests that RAL GTPase inhibition will be an important treatment strategy for tumors harboring RAS glycine to cysteine (G12C) or glycien to valine (G12V) mutations, which are commonly found in NSCLC and pancreatic cancer. Review RAS GTPase overviewRAS is the most extensively studied GTPase [1] . It is known to regulate various cellular functions, including proliferation, survival, growth, migration, differentiation and cytoskeletal dynamics [2][3][4] (Figure 1). Not coincidentally, increased activities of all of these processes are required by tumor cells to promote tumor growth. Activating oncogenic RAS mutations lead to treatment resistance in various tumor models and poor patient outcomes [3,[5][6][7][8][9] . Three human RAS genes have been identified: HRAS, KRAS, and NRAS [1,2] . These encode the related proteins HRAS, KRAS and NRAS, respectively, of 189 amino acids in length [1,4] . KRAS exists as two isoforms, 4A and 4B, which are generated by alternative exon splicing [10] . These different RAS genes are well known to have differential cellular specificities and intrinsic transforming potentials [3,4,10] .In normal cells, RAS proteins act as molecular switches for critical cellular functions. RAS proteins are activated by upstream receptors such as receptor tyrosine kinases * To whom correspondence should be addressed. E-mail dan.theodorescu@ucdenver.edu Received 2014-08-07 Accepted 2014-10-30 Figure 1. RAS GTPase activation and downstream signaling. The cartoon shows the mechanism of RAS GTPase activation by upstream stimuli and numerous downstream effectors stimulated by activated RAS. RAS regulates critical cellular functions through these effectors. Constitutive RAS activation due to mutations leads to protumorigenic signaling through these effectors.

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“…2), similar to active RalA-enhanced axon extension involving the exocyst (Lalli and Hall, 2005). To determine whether RalA regulates neuroblast morphology and migration through the exocyst, we electroporated CA RalA or an Exo84-uncoupled CA RalA version (RalAQ72LA48W) (Fukai et al, 2003;Hazelett et al, 2011) and examined RMS neuroblasts 5 days later. To assess the specificity of the effects caused by Exo84-uncoupled RalA, we also electroporated CA RalA uncoupled from RalBP1 (RalAQ72LD49N), another Ral effector (Jullien-Flores et al, 2000;Lalli and Hall, 2005) (Fig.…”

Section: Deletion Of Rala Affects Neuroblast Orientation and Morpholomentioning

confidence: 99%

“…Small GTPases coordinate these events to establish cell polarity in response to intra-and extracellular cues (Mellman and Nelson, 2008;McCaffrey and Macara, 2009;Hall and Lalli, 2010). Among these, the Ras-like GTPase Ral, of which there are two isoforms, RalA and RalB, has emerged as an important polarity regulator in a variety of contexts, including basolateral membrane trafficking and tight junction formation in epithelial cells (Shipitsin and Feig, 2004;Hazelett et al, 2011), polarized migration of fibroblasts and cancer cells (Rossé et al, 2006;Spiczka and Yeaman, 2008) and tumorigenesis (Camonis and White, 2005;Lim et al, 2005;Oxford et al, 2005;Bodemann and White, 2008;Hazelett and Yeaman, 2012). During brain development, Ral is involved in asymmetric division of neuroblasts (Carmena et al, 2011), neuronal migration in the neocortex (Jossin and Cooper, 2011), neurite branching (Lalli and Hall, 2005) and activity-dependent spine growth (Teodoro et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

RalA promotes a direct exocyst-Par6 interaction to regulate polarity in neuronal development

Das

Gajendra

Falenta

et al. 2013

Journal of Cell Science

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Cell polarization is essential for neuronal development in both the embryonic and postnatal brain. Here, using primary cultures, in vivo postnatal electroporation and conditional genetic ablation, we show that the Ras-like small GTPase RalA and its effector, the exocyst, regulate the morphology and polarized migration of neural progenitors derived from the subventricular zone, a major neurogenic niche in the postnatal brain. Active RalA promotes the direct binding between the exocyst subunit Exo84 and the PDZ domain of Par6 through a non-canonical PDZ-binding motif. Blocking the Exo84-Par6 interaction impairs polarization in postnatal neural progenitors and cultured embryonic neurons. Our results provide the first in vivo characterization of RalA function in the mammalian brain and highlight a novel molecular mechanism for cell polarization. Given that the exocyst and the Par complex are conserved in many tissues, the functional significance of their interaction and its regulation by RalA are likely to be important in a wide range of polarization events.

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RalA and RalB differentially regulate development of epithelial tight junctions

Cited by 33 publications

References 51 publications

The Exocyst at a Glance

The Exocyst at a Glance

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

RalA promotes a direct exocyst-Par6 interaction to regulate polarity in neuronal development

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