Characterization of Interactions of Adapter Protein RAPL/Nore1B with RAP GTPases and Their Role in T Cell Migration

Miertzschke, Mandy; Stanley, Paula; Bunney, Tom D.; Rodrigues‐Lima, Fernando; Hogg, Nancy; Katan, Matilda

doi:10.1074/jbc.m704361200

Cited by 38 publications

(41 citation statements)

References 52 publications

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“…Regulates lymphocyte adhesion, T cell migration, T cell receptor regulation [84,86,186] Controls the directional migration of vascular endothelial cells [6] arising from alternative splicing and differential promoter usage. Among the RASSF1 subtypes, 1A and 1C are the most extensively studied members with both localized to microtubules and involved in regulation of growth and migration [14,15].…”

Section: Kdamentioning

confidence: 99%

RASSF tumor suppressor gene family: Biological functions and regulation

et al. 2014

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a b s t r a c tGenetic changes through allelic loss and nucleic acid or protein modifications are the main contributors to loss of function of tumor suppressor proteins. In particular, epigenetic silencing of genes by promoter hypermethylation is associated with increased tumor severity and poor survival. The RASSF (Ras association domain family) family of proteins consists of 10 members, many of which are tumor suppressor proteins that undergo loss of expression through promoter methylation in numerous types of cancers such as leukemia, melanoma, breast, prostate, neck, lung, brain, colorectal and kidney cancers. In addition to their tumor suppressor function, RASSF proteins act as scaffolding agents in microtubule stability, regulate mitotic cell division, modulate apoptosis, control cell migration and cell adhesion, and modulate NFjB activity and the duration of inflammation. The ubiquitous functions of these proteins highlight their importance in numerous physiological pathways. In this review, we will focus on the biological roles of the RASSF family members and their regulation.

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Section: Kdamentioning

confidence: 99%

RASSF tumor suppressor gene family: Biological functions and regulation

et al. 2014

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“…Most of these proteins have been identified by their ability to bind to Rap-GTP via RA domains (Frische and Zwartkruis, 2010). However, with the exception of Riam and RapL, which can regulate integrin complexes (Ebisuno et al, 2010;Katagiri et al, 2006;Katagiri et al, 2003;Kinashi and Katagiri, 2004;Lafuente and Boussiotis, 2006;Lafuente et al, 2004;Lee et al, 2009;Miertzschke et al, 2007;Watanabe et al, 2008), it is unclear how most of these different proteins bring about Rap-induced changes. Furthermore, it is not yet understood how the functions of these individual proteins relate to one another.…”

Section: Introductionmentioning

confidence: 99%

“…Although the outcome of Rap activation on cell adhesion and actin remodelling is well established, the mechanisms by which these occur are less well understood, but are beginning to be elucidated. A number of proteins, including Riam (Lafuente and Boussiotis, 2006;Lafuente et al, 2004;Lee et al, 2009;Watanabe et al, 2008), RapL (Ebisuno et al, 2010;Katagiri et al, 2006;Katagiri et al, 2003;Kinashi and Katagiri, 2004;Miertzschke et al, 2007), Arap3 (Krugmann et al, 2004;Raaijmakers et al, 2007), Tiam1 (Arthur et al, 2004), AF6 (Boettner et al, 2000;Zhang et al, 2005), and Radil (Ahmed et al, 2010;Smolen et al, 2007) have been proposed to be Rap effector proteins that mediate aspects of Rap-induced changes to integrins or the cytoskeleton (Bos, 2005;Raaijmakers and Bos, 2009). Most of these proteins have been identified by their ability to bind to Rap-GTP via RA domains (Frische and Zwartkruis, 2010).…”

Section: Introductionmentioning

confidence: 99%

Ezrin is required for efficient Rap1-induced cell spreading

Ross

Post

Raaijmakers

et al. 2011

Journal of Cell Science

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SummaryThe Rap family of small GTPases regulate the adhesion of cells to extracellular matrices. Several Rap-binding proteins have been shown to function as effectors that mediate Rap-induced adhesion. However, little is known regarding the relationships between these effectors, or about other proteins that are downstream of or act in parallel to the effectors. To establish whether an array of effectors was required for Rap-induced cell adhesion and spreading, and to find new components involved in Rap-signal transduction, we performed a small-scale siRNA screen in A549 lung epithelial cells. Of the Rap effectors tested, only Radil blocked Rap-induced spreading. Additionally, we identified a novel role for Ezrin downstream of Rap1. Ezrin was necessary for Rap-induced cell spreading, but not Rap-induced cell adhesion or basal adhesion processes. Furthermore, Ezrin depletion inhibited Rap-induced cell spreading in several cell lines, including primary human umbilical vein endothelial cells. Interestingly, Radixin and Moesin, two proteins with high homology to Ezrin, are not required for Rap-induced cell spreading and cannot compensate for loss of Ezrin to rescue Rap-induced cell spreading. Here, we present a novel function for Ezrin in Rap1-induced cell spreading and evidence of a non-redundant role of an ERM family member.

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“…However, we did not investigate the role of the Rap2 GTPase as a potential mediator of a L b 2 activation and TEM in Rap1-unresponsive a 4 b 1 + CLL cells. To do so seemed important because Rap2 is involved in the migration of normal lymphocytes (27), is activated by chemokine stimulation, and has functions that overlap with those of Rap1 (28,29). Examination of 16 CLL samples showed that Rap2 levels were much lower than levels of Rap1 (4.5 6 0.7 versus 172 6 17 ng/5 3 10 6 cells) (Supplemental Fig.…”

Section: Rap2 Is Expressed At Low Levels and Is Not Gtp Loaded In Cllmentioning

confidence: 99%

Chemokine Unresponsiveness of Chronic Lymphocytic Leukemia Cells Results from Impaired Endosomal Recycling of Rap1 and Is Associated with a Distinctive Type of Immunological Anergy

Pye

Rubio

Pusch

et al. 2013

The Journal of Immunology

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Trafficking of malignant lymphocytes is fundamental to the biology of chronic lymphocytic leukemia (CLL). Transendothelial migration (TEM) of normal lymphocytes into lymph nodes requires the chemokine-induced activation of Rap1 and αLβ2 integrin. However, in most cases of CLL, Rap1 is refractory to chemokine stimulation, resulting in failed αLβ2 activation and TEM unless α4β1 is coexpressed. In this study, we show that the inability of CXCL12 to induce Rap1 GTP loading in CLL cells results from failure of Rap1-containing endosomes to translocate to the plasma membrane. Furthermore, failure of chemokine-induced Rap1 translocation/GTP loading was associated with a specific pattern of cellular IgD distribution resembling that observed in normal B cells anergized by DNA-based Ags. Anergic features and chemokine unresponsiveness could be simultaneously reversed by culturing CLL cells ex vivo, suggesting that these two features are coupled and driven by stimuli present in the in vivo microenvironment. Finally, we show that failure of Rap1 translocation/GTP loading is linked to defective activation of phospholipase D1 and its upstream activator Arf1. Taken together, our findings indicate that chemokine unresponsiveness in CLL lymphocytes results from failure of Arf1/phospholipase D1–mediated translocation of Rap1 to the plasma membrane for GTP loading and may be a specific feature of anergy induced by DNA Ags.

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Characterization of Interactions of Adapter Protein RAPL/Nore1B with RAP GTPases and Their Role in T Cell Migration

Cited by 38 publications

References 52 publications

RASSF tumor suppressor gene family: Biological functions and regulation

RASSF tumor suppressor gene family: Biological functions and regulation

Ezrin is required for efficient Rap1-induced cell spreading

Chemokine Unresponsiveness of Chronic Lymphocytic Leukemia Cells Results from Impaired Endosomal Recycling of Rap1 and Is Associated with a Distinctive Type of Immunological Anergy

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