An image-based RNAi screen identifies SH3BP1 as a key effector of Semaphorin 3E–PlexinD1 signaling

Tata, Aleksandra; Stoppel, David C.; Hong, Shangyu; Ben-Zvi, Ayal; Gu, Chenghua

doi:10.1083/jcb.201309004

Cited by 26 publications

(36 citation statements)

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“…Furthermore, the inhibitory effect of sema3e on b 1 integrin in previous reports (24) may be related to simultaneous inhibition of Rap1 and a 4 b 1 integrin activation (13,26). Small GTPase Rac, which also promotes cell adhesion processes and F-actin polymerization, is inhibited by plexin D1 (32). We also found that sema3e inhibited chemokine-induced Rac activation (Y. Ueda, unpublished observations), which could contribute to cell detachment due to actin collapse.…”

Section: Discussionmentioning

confidence: 54%

“…Previous studies reported rapid cell collapse of endothelial cells in response to sema3e/plexin D1 signals and an associated downregulation of Rac activation (32,33). Rac can directly activate integrins (34) or indirectly strengthen integrin-dependent adhesion via cytoskeletal reorganization and morphological changes, such as cell spreading (35).…”

Section: Constitutively Active Rac Did Not Rescue Sema3e-mediated Detmentioning

confidence: 99%

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Sema3e/Plexin D1 Modulates Immunological Synapse and Migration of Thymocytes by Rap1 Inhibition

Ueda

Kondo

Ozawa

et al. 2016

The Journal of Immunology

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Regulation of thymocyte trafficking plays an important role during thymic selection, but our understanding of the molecular mechanisms underlying these processes is limited. In this study, we demonstrated that class III semaphorin E (sema3e), a guidance molecule during neural and vascular development, directly inhibited Rap1 activation and LFA-1–dependent adhesion through the GTPase-activating protein activity of plexin D1. Sema3e inhibited Rap1 activation of thymocytes in response to chemokines and TCR stimulation, LFA-mediated adhesion, and T cell–APC interactions. Immunological synapse (IS) formation in mature thymocytes on supported lipid bilayers was also attenuated by sema3e. Impaired IS formation was associated with reduced Rap1 activation on the contact surface and cell periphery. Moreover, a significant increase of CD4+ thymocytes was detected in the medulla of mice with T cell lineage–specific deletion of plexin D1. Two-photon live imaging of thymic explants and slices revealed enhanced Rap1 activation and migration of CD69+ double-positive and single-positive cells with plexin D1 deficiency. Our results demonstrate that sema3e/plexin D1 modulates IS formation and Ag-scanning activities of thymocytes within thymic tissues.

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Section: Discussionmentioning

confidence: 54%

Section: Constitutively Active Rac Did Not Rescue Sema3e-mediated Detmentioning

confidence: 99%

Sema3e/Plexin D1 Modulates Immunological Synapse and Migration of Thymocytes by Rap1 Inhibition

Ueda

Kondo

Ozawa

et al. 2016

The Journal of Immunology

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“…Therefore, RacGAPs are also expected to modulate neuronal morphogenesis and synaptic functions. Indeed, through a reduction of Rac1 activity, the Rac1 GAP SH3BP1 was shown to mediate a morphological collapse of developing neurons (Tata et al, 2014).…”

Section: Control By Signalingmentioning

confidence: 99%

Different functional modes of BAR domain proteins in formation and plasticity of mammalian postsynapses

Kessels

Qualmann

2015

Journal of Cell Science

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A plethora of cell biological processes involve modulations of cellular membranes. By using extended lipid-binding interfaces, some proteins have the power to shape membranes by attaching to them. Among such membrane shapers, the superfamily of Bin–Amphiphysin–Rvs (BAR) domain proteins has recently taken center stage. Extensive structural work on BAR domains has revealed a common curved fold that can serve as an extended membrane-binding interface to modulate membrane topologies and has allowed the grouping of the BAR domain superfamily into subfamilies with structurally slightly distinct BAR domain subtypes (N-BAR, BAR, F-BAR and I-BAR). Most BAR superfamily members are expressed in the mammalian nervous system. Neurons are elaborately shaped and highly compartmentalized cells. Therefore, analyses of synapse formation and of postsynaptic reorganization processes (synaptic plasticity) – a basis for learning and memory formation – has unveiled important physiological functions of BAR domain superfamily members. These recent advances, furthermore, have revealed that the functions of BAR domain proteins include different aspects. These functions are influenced by the often complex domain organization of BAR domain proteins. In this Commentary, we review these recent insights and propose to classify BAR domain protein functions into (1) membrane shaping, (2) physical integration, (3) action through signaling components, and (4) suppression of other BAR domain functions.

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“…Comparing the magnitude of fold change between KLF1 and Nan-KLF1 DEGs shows most DEGs are differentially responsive between sample groups (Figure 3.5A). For example, some known KLF1 target genes, such as Alas2 (Tallack & Perkins, 2010a) and Klf10 (Funnell et al, 2007c), are activated equally (4.4-fold & ~100-fold up-regulated respectively) by KLF1 and Nan-KLF1, while other KLF1 target genes such as Alad (Tata et al, 2014) and Hbb-b1 (Miller & Bieker, 1993) are more responsive to KLF1. Finally a third set of genes, not regulated by KLF1, are responsive to Nan-KLF1; this set includes Dusp7, Sh3bp1 and Zfp36.…”

Section: ________mentioning

confidence: 99%

“…it is an example of a Category IV motif (Figure 3.4A). Sh3bp1 is ectopically activated by Nan-KLF1; it is a RhoGAP protein normally expressed by neural tissues (Figure 3.5C) (Tata et al, 2014). Expression in erythroid cells has not previously been reported and aberrant expression could lead to dysregulated signalling.…”

Section: ________mentioning

confidence: 99%

Investigating the Molecular Pathogenesis of Inherited Childhood Anaemia

Ilsley¹

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Krüppel-like factors (KLFs) are a group of 17 transcription factors with diverse functions such as early embryo patterning, organogenesis and tissue homoeostasis. All 17 members contain highlyconserved DNA-binding domains consisting of three C-terminal C2H2-type zinc fingers. This high level of conservation allows all members of the KLF family to bind to a 9 base pair CACCC-box DNA sequence (CCM CRC CCN) which is commonly found in many tissue-specific gene promoters and enhancers. The activity of each member of the KLF family is largely determined by a more variable N-terminal domain through which they interact with co-factors such as p300 and C-terminal binding protein 2 (CtBP2).Many KLFs are often expressed in the same cells. In these situations, they can form transcriptional networks where they coordinate to control developmental programs. For example, KLF2, KLF4, and KLF5 work redundantly in embryonic stem cells where they regulate key pluripotency genes such as Nanog to maintain the 'stemness' of the cell. Multiple KLFs are expressed during erythropoiesis, the ongoing production of red blood cells, where it is likely that they form transcriptional networks to control differentiation.Krüppel-like factor 1 (KLF1) is an erythroid-specific transcription factor that is responsible for coordinating the expression of a large cohort of genes required for nearly all aspects of erythropoiesis. As the founding member of the KLF group, KLF1 contains three C-terminal C2H2-type zinc fingers that bind to DNA and an N-terminal proline-rich activation domain that interacts with co-factors to initiate transcription of target genes.This thesis investigates the molecular mechanisms of Klf1 binding specificity to DNA and how this is affected by mutations, and by competition between family members.A disease that is known as Congenital Dyserythropoietic anaemia type IV (CDAIV) is a rare autosomal-dominant inherited erythrocyte disorder characterised by ineffective erythropoiesis and haemolysis. CDAIV is caused by a point mutation in the second zinc finger of KLF1 which results in substitution of an amino acid predicted to bind to DNA.A mouse carrying a point mutation in the corresponding amino acid residue in murine Klf1 to that mutated in CDAIV patients has been previously generated in an ENU screen. This mouse displays a semi-dominant haemolytic anaemia and is named 'Nan' for 'neonatal anaemia'. The Nan mouse shares a similar phenotype to that of patients with CDAIV and hereditary spherocytosis.Incredibly, both the 'Nan' and CDAIV mutations cause disease which is far more severe than that of commonly occurring Klf1 haploinsufficiency.ii ChIP-seq analysis in cell lines developed to model Klf1 mutations identified aberrant DNAbinding events genome-wide for both the mouse 'Nan' mutation and the human CDAIV mutation.Next-generation sequencing of newly-synthesised RNA (4sU-RNA-seq) reveals ectopic transcriptional consequences of this aberrant binding. Novel sequence specificity of the mutant protein was confirmed by performi...

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An image-based RNAi screen identifies SH3BP1 as a key effector of Semaphorin 3E–PlexinD1 signaling

Abstract: The RhoGAP protein SH3BP1 mediates Sema3E-induced cell collapse through interaction with PlexinD1 and regulation of Rac1 activity.

Cited by 26 publications

References 50 publications

Sema3e/Plexin D1 Modulates Immunological Synapse and Migration of Thymocytes by Rap1 Inhibition

Sema3e/Plexin D1 Modulates Immunological Synapse and Migration of Thymocytes by Rap1 Inhibition

Different functional modes of BAR domain proteins in formation and plasticity of mammalian postsynapses

Investigating the Molecular Pathogenesis of Inherited Childhood Anaemia

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