Rap1-interacting adapter molecule (RIAM) associates with the plasma membrane via a proximity detector

Wynne, Joseph; Wu, Jiangxue; Su, Wenjuan; Mor, Adam; Patsoukis, Nikolaos; Boussiotis, Vassiliki A.; Hubbard, Stevan R.; Philips, Mark R.

doi:10.1083/jcb.201201157

Cited by 56 publications

(106 citation statements)

References 43 publications

(66 reference statements)

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“…Similar results were also obtained with a cherry-tagged version of the Ras-associating and Pleckstrin homology domains of Rap1-GTP-interacting adaptor molecule (cherry-RIAM-RAPH), an alternative biosensor (Fig. S1B) (7). In primary human T cells, Rap1 GST pull-down assay shows that Rap1-GTP is increased nearly twofold (Fig.…”

Section: Resultssupporting

confidence: 68%

PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

Strazza

Azoulay-Alfaguter

Peled

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase Ce 1 (PLCe1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1α)-induced Rap1 activation. We have shown that SDF-1α-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLCe1 was necessary for SDF-1α-induced adhesion using shear stress, cell morphology alterations, and crawling on intercellular adhesion molecule 1 (ICAM-1)-expressing cells. Structurefunction experiments to separate the dual-enzymatic function of PLCe1 uncover necessary contributions of the CDC25, Pleckstrin homology, and Ras-associating domains, but not phospholipase activity, to this pathway. In the mouse model of delayed type hypersensitivity, we have shown an essential role for PLCe1 in T-cell migration to inflamed skin, but not for cytokine secretion and proliferation in regional lymph nodes. Our results reveal a signaling pathway where SDF-1α induces T-cell adhesion through activation of PLCe1, suggesting that PLCe1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs.

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Section: Resultssupporting

confidence: 68%

PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

Strazza

Azoulay-Alfaguter

Peled

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…This phenomenon has been observed in Rap1-interacting adaptor molecule (RIAM), which contains both Rasassociation and PH domains and requires both Rap1 GTPase interaction, mediated by the Ras-association domain, and PtdInsP binding, mediated by the PH domain, for cell surface recruitment in activated T-cells (Wynne et al, 2012). The previous findings showing that SNX27 can associate with a small GTPase through its Ras-association-domain-related F1 module (Balana et al, 2013;Ghai et al, 2013;Loo et al, 2014), and the discovery here that it can bind PtdInsP species through the F3 module present a tempting parallel to the RIAM system, and suggests that PtdInsP, cargo and GTPase interactions may co-operatively contribute to membrane localization of SNX27 following certain cell stimuli.…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide binding by the SNX27 FERM domain regulates localisation at the immune synapse of activated T-cells

Ghai

Tello-Lafoz

Norwood

et al. 2014

Journal of Cell Science

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Sorting nexin 27 (SNX27) controls the endosomal-to-cell-surface recycling of diverse transmembrane protein cargos. Crucial to this function is the recruitment of SNX27 to endosomes which is mediated by the binding of phosphatidylinositol-3-phosphate (PtdIns3P) by its phox homology (PX) domain. In T-cells, SNX27 localizes to the immunological synapse in an activation-dependent manner, but the molecular mechanisms underlying SNX27 translocation remain to be clarified. Here, we examined the phosphoinositide-lipid-binding capabilities of full-length SNX27, and discovered a new PtdInsPbinding site within the C-terminal 4.1, ezrin, radixin, moesin (FERM) domain. This binding site showed a clear preference for bi-and tri-phosphorylated phophoinositides, and the interaction was confirmed through biophysical, mutagenesis and modeling approaches. At the immunological synapse of activated T-cells, cell signaling regulates phosphoinositide dynamics, and we find that perturbing phosphoinositide binding by the SNX27 FERM domain alters the SNX27 distribution in both endosomal recycling compartments and PtdIns(3,4,5)P 3 -enriched domains of the plasma membrane during synapse formation. Our results suggest that SNX27 undergoes dynamic partitioning between different membrane domains during immunological synapse assembly, and underscore the contribution of unique lipid interactions for SNX27 orchestration of cargo trafficking.

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“…RIAM functions downstream of Rap1 in inside-out integrin signaling. In vitro data have suggested that RIAM interacts with guanosine triphosphate (GTP)-bound Rap1, but not with guanosine diphosphate-bound Rap1, and exhibits weak, rather nonspecific binding to other Ras GTPases (1,14). The RA domain of RIAM has also been shown to interact with Ras by pull-down experiments using a recombinant glutathione S-transferase (GST)-tagged RIAM RA domain and lysates from NIH 3T3 cells transfected with Myc-tagged RasV12.…”

Section: Interactions Of the Ra And Ph Domainsmentioning

confidence: 99%

The adaptor molecule RIAM integrates signaling events critical for integrin-mediated control of immune function and cancer progression

et al. 2017

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Lymphocyte activation requires adhesion to antigen-presenting cells. This is a critical event linking innate and adaptive immunity. Lymphocyte adhesion is accomplished through LFA-1, which must be activated by a process referred to as inside-out integrin signaling. Among the few signaling molecules that have been implicated in inside-out integrin activation in hematopoietic cells are the small guanosine triphosphatase (GTPase) Rap1 and its downstream effector Rap1-interacting molecule (RIAM), a multidomain protein that defined the Mig10-RIAM-lamellipodin (MRL) class of adaptor molecules. Through its various domains, RIAM is a critical node of signal integration for activation of T cells, recruits monomeric and polymerized actin to drive actin remodeling and cytoskeletal reorganization, and promotes inside-out integrin signaling in T cells. As a regulator of inside-out integrin activation, RIAM affects multiple functions of innate and adaptive immunity. The effects of RIAM on cytoskeletal reorganization and integrin activation have implications in cell migration and trafficking of cancer cells. We provide an overview of the structure and interactions of RIAM, and we discuss the implications of RIAM functions in innate and adaptive immunity and cancer.

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Rap1-interacting adapter molecule (RIAM) associates with the plasma membrane via a proximity detector

Abstract: The Ras association and PH domains of RIAM function as a proximity detector for activated Rap1 and PI(4,5)P2.

Cited by 56 publications

References 43 publications

PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

Phosphoinositide binding by the SNX27 FERM domain regulates localisation at the immune synapse of activated T-cells

The adaptor molecule RIAM integrates signaling events critical for integrin-mediated control of immune function and cancer progression

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