Correction: Annular PIP3 accumulation controls actin architecture and modulates cytotoxicity at the immunological synapse

Floc’h, Audrey Le; Tanaka, Yoshihiko; Bantilan, Niels S.; Voisinne, Guillaume; Altan‐Bonnet, Grégoire; Fukui, Yoshihiro; Huse, Morgan

doi:10.1084/jem.2013132403102017c

Cited by 3 publications

(6 citation statements)

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“…The guanine nucleotide exchange factor DOCK2 is found to be associated with CrkL in leukemia cell lines, 96 which in turn binds phospho‐Cas‐L via its SH2 domain downstream of TCR activation 50 , 52 . Thus, we speculate that a Cas‐L‐CrkL‐DOCK2‐Rac multiprotein complex can that directly activate the small GTPase Rac downstream of TCR activation, thus promoting f‐actin polymerization through activation of the WAVE2 complex 96 , 97 , 98 . Furthermore, a recent study 99 reported that although early TCR microclusters are able to activate T‐cell cytokine expression, centralization of TCR microclusters is more important for Notch‐ADAM10‐Vav1‐dependent T‐cell proliferation.…”

Section: Discussionmentioning

confidence: 89%

Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

et al. 2016

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The immunological synapse formed between a T cell and an antigen presenting cell is important for cell-cell communication during T cell mediated immune responses. Immunological synapse formation begins with stimulation of the T cell receptor (TCR). TCR microclusters are assembled and transported to the center of the immunological synapse in an actin polymerization-dependent process. However, the physical link between TCR and actin remains elusive. Here we show that lymphocyte-specific Crk-associated substrate (Cas-L), a member of a force sensing protein family, is required for transport of TCR microclusters and for establishing synapse stability. We found that Cas-L is phosphorylated at TCR microclusters in an actin polymerization-dependent fashion. Furthermore, Cas-L participates in a positive feedback loop leading to amplification of Ca2+ signaling, inside-out integrin activation, and actomyosin contraction. We propose a new role for Cas-L in T cell activation as a mechanical transducer linking TCR microclusters to the underlying actin network and coordinating multiple actin dependent structures in the immunological synapse. Our studies highlight the importance of mechanotransduction processes in T cell mediated immune responses.

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Section: Discussionmentioning

confidence: 89%

Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

et al. 2016

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“…) (Cote et al, ; Kunisaki et al, ). By directly binding to the DHR‐1 domain, PIP3 recruits cytoplasmic DOCK2 to plasma membrane (Kunisaki et al, ; Le Floc'h et al, ). This translocation and polarization is important for the Rac GEF activation.…”

Section: Dock2 Binding Proteinsmentioning

confidence: 99%

Dedicator of Cytokinesis 2 in Cell Signaling Regulation and Disease Development

Guo

Chen

2017

Journal Cellular Physiology

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Dedicator of cytokinesis 2 (DOCK2) is a CDM family protein containing DOCK homology region (DHR)-1 and DHR-2, Src-homology 3 (SH3) domain, and C-terminal polybasic amino acid cluster. The CDM family consists of 11 mammalian members and is classified into four subfamilies, the DOCK-A, -B, -C, and -D. DOCK2 is a member of DOCK-A subfamily and an atypical guanine exchange factor regulating the loading of GTP to activate Rac. It is primarily found in peripheral blood, spleen, and thymus and mainly expressed in lymphocytes and macrophages of various organs. DOCK2 is also expressed in microglial in brain and is induced in neointima smooth muscle following vascular injury. Functionally, DOCK2 is involved in cell motility, polarity, adhesion, proliferation, and apoptosis. It is essential for lymphocyte migration and activation as well as neutrophil chemotaxis. DOCK2 also regulates the differentiation of natural killer T cells, type 2 T helper cells, and plasmacytoid dendritic cells. In addition, it is important for the growth of B cell lymphoma and prostate cancer cells. Deletion of DOCK2 enables long-term cardiac allograft survival. Moreover, DOCK2 is associated with the Alzheimer Disease, HIV development, and the early-onset of invasive infections. Recently, we found that DOCK2 plays a critical role in SMC phenotypic modulation and vascular remodeling. In this review, we will briefly summarize recent advancement of DOCK2 function. J. Cell. Physiol. 232: 1931-1940, 2017. © 2016 Wiley Periodicals, Inc.

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“…We then focused our attention on early signaling events important for cytoskeletal rearrangement and cytotoxic granules release in NK cells. In particular, at the IS, the activity of small GTPases, such as Rac1, RhoA and RhoG, together with other mediators and adaptors, is critical for the efficient degranulation after target cell recognition [ 41 – 44 ]. Indeed, their activity is required for the synaptic F-actin remodeling, and has a strong impact on cytotoxic granules release [ 41 – 44 ].…”

Section: Resultsmentioning

confidence: 99%

“…In particular, at the IS, the activity of small GTPases, such as Rac1, RhoA and RhoG, together with other mediators and adaptors, is critical for the efficient degranulation after target cell recognition [ 41 – 44 ]. Indeed, their activity is required for the synaptic F-actin remodeling, and has a strong impact on cytotoxic granules release [ 41 – 44 ]. Of note, Rac1 and RhoA have been identified as substrates of the E3 ubiquitin Cullin-Ring ligases, and their expression and function is increased after neddylation inhibition in different models [ 44 , 50 , 51 ].…”

Section: Resultsmentioning

confidence: 99%

“…Our data indicate that MLN4924/Pevonedistat, used in the nanomolar range of concentration, upregulates NK cell-mediated degranulation and killing towards MM cells; moreover, it potentiates Daratumumab and Elotuzumab-mediated NK cell degranulation. Mechanistically, neddylation inhibition significantly increases the expression of Rac1 and RhoA GTPases in NK cells, critical mediators for an efficient degranulation at the immunological synapse (IS) of cytotoxic lymphocytes [ 41 – 44 ], and augments the levels of F-actin and the efficiency of perforin polarization in NK cells contacting target cells.…”

Section: Introductionmentioning

confidence: 99%

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NEDD8-activating enzyme inhibition potentiates the anti-myeloma activity of natural killer cells

et al. 2023

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Natural Killer (NK) cells act as important regulators in the development and progression of hematological malignancies and their suppressor activity against Multiple Myeloma (MM) cells has been confirmed in many studies. Significant changes in the distribution of NK cell subsets and dysfunctions of NK cell effector activities were described in MM patients and correlated with disease staging. Thus, restoring or enhancing the functionality of these effectors for the treatment of MM represents a critical need. Neddylation is a post-translational modification that adds a ubiquitin-like molecule, NEDD8, to the substrate protein. One of the outcomes is the activation of the Cullin Ring Ligases (CRLs), a class of ubiquitin-ligases that controls the degradation of about 20% of proteasome-regulated proteins. Overactivation of CRLs has been described in cancer and can lead to tumor growth and progression. Thus, targeting neddylation represents an attractive approach for cancer treatment. Our group has recently described how pharmacologic inhibition of neddylation increases the expression of the NKG2D activating receptor ligands, MICA and MICB, in MM cells, making these cells more susceptible to NK cell degranulation and killing. Here, we extended our investigation to the direct role of neddylation on NK cell effector functions exerted against MM. We observed that inhibition of neddylation enhanced NK cell-mediated degranulation and killing against MM cells and improved Daratumumab/Elotuzumab-mediated response. Mechanistically, inhibition of neddylation increased the expression of Rac1 and RhoA GTPases in NK cells, critical mediators for an efficient degranulation at the immunological synapse of cytotoxic lymphocytes, and augmented the levels of F-actin and perforin polarization in NK cells contacting target cells. Moreover, inhibition of neddylation partially abrogated TGFβ-mediated repression of NK cell effector activity. This study describes the role of neddylation on NK cell effector functions and highlights the positive immunomodulatory effects achieved by the inhibition of this pathway in MM.

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Correction: Annular PIP3 accumulation controls actin architecture and modulates cytotoxicity at the immunological synapse

Cited by 3 publications

References 0 publications

Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

Dedicator of Cytokinesis 2 in Cell Signaling Regulation and Disease Development

NEDD8-activating enzyme inhibition potentiates the anti-myeloma activity of natural killer cells

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