A reverse signaling pathway downstream of Sema4A controls cell migration via Scrib

Sun, Tianliang; Liu, Yang; Kaur, Harmandeep; Pestel, Jenny; Looso, Mario; Nolte, Hendrik; Krasel, Cornelius; Heil, Daniel P.; Krishnan, Ramesh Kumar; Santoni, Marie-Josée; Borg, Jean-Paul; Bünemann, Moritz; Offermanns, Stefan; Swiercz, Jakub M.; Worzfeld, Thomas

doi:10.1083/jcb.201602002

Cited by 42 publications

(38 citation statements)

References 90 publications

(114 reference statements)

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“…Similarly, in response to directional cues, MCF-10A epithelial cells require Scribble to recruit Rac1 and Cdc42 to the leading edge to form stable lamellipodial protrusions (Dow et al, 2007). A promigratory function for Scribble has also been shown in dendritic cells and certain cancer cell lines, acting downstream of the interaction of Plexin-B1 with its transmembrane receptor Sema4A (Sun et al, 2017). Here, it is suggested that the interaction with Sema4A leads to reduced binding of Scribble to β-PIX, with consequences for polarized Cdc42 and Rac activity (Sun et al, 2017).…”

Section: Scribble Also Regulates Cell Migration and Metastasismentioning

confidence: 99%

Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation

Bonello

Peifer

2018

Journal of Cell Biology

121

127

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Key events ranging from cell polarity to proliferation regulation to neuronal signaling rely on the assembly of multiprotein adhesion or signaling complexes at particular subcellular sites. Multidomain scaffolding proteins nucleate assembly and direct localization of these complexes, and the protein Scribble and its relatives in the LAP protein family provide a paradigm for this. Scribble was originally identified because of its role in apical–basal polarity and epithelial integrity in Drosophila melanogaster. It is now clear that Scribble acts to assemble and position diverse multiprotein complexes in processes ranging from planar polarity to adhesion to oriented cell division to synaptogenesis. Here, we explore what we have learned about the mechanisms of action of Scribble in the context of its multiple known interacting partners and discuss how this knowledge opens new questions about the full range of Scribble protein partners and their structural and signaling roles.

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Section: Scribble Also Regulates Cell Migration and Metastasismentioning

confidence: 99%

Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation

Bonello

Peifer

2018

Journal of Cell Biology

121

127

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“…Moreover, another report showed that SEMA4A on the surface of immune cells engaged in trans with NRP1 expressed on Treg lymphocytes, promoting their immunosuppressive activity [41]. SEMA4A also contains an intracellular domain that can mediate reverse signaling cascades into dendritic cells, for instance controlling their migration [42]. The role of SEMA4A in cancer context is still unclear.…”

Section: Semaphorin 4amentioning

confidence: 99%

Semaphorin Signaling in Cancer-Associated Inflammation

Franzolin

Tamagnone

2019

IJMS

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The inflammatory and immune response elicited by the growth of cancer cells is a major element conditioning the tumor microenvironment, impinging on disease progression and patients’ prognosis. Semaphorin receptors are widely expressed in inflammatory cells, and their ligands are provided by tumor cells, featuring an intense signaling cross-talk at local and systemic levels. Moreover, diverse semaphorins control both cells of the innate and the antigen-specific immunity. Notably, semaphorin signals acting as inhibitors of anti-cancer immune response are often dysregulated in human tumors, and may represent potential therapeutic targets. In this mini-review, we provide a survey of the best known semaphorin regulators of inflammatory and immune cells, and discuss their functional impact in the tumor microenvironment.

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“…Enrichment analysis of the downregulated genes implicated GO term pathways predominantly involved in cell migration, cell motility, locomotion, and localization (Figure B). The genes comprising these GO terms include C5ar1 (a receptor for C5a, a known chemoattractant) as well as multiple genes associated with tumor metastasis ( Cmtm3, Nr4a1, Sparc, Tnf, Gpnb ) and with chemotaxis, adhesion, and cytoskeletal interactions ( Fermt3, Rhod, Cd151, Sema4a, Plxnd1 ).…”

Section: Resultsmentioning

confidence: 99%

“…The gene array analyses performed on RNA derived from graft‐infiltrating mononuclear cells add to the literature by associating numerous genes previously shown to participate in chemotaxis, angiogenesis, adhesion, and cancer metastasis with C5aR1. Additional studies to be performed by our laboratory, among others, are required to test the specific hypothesis that these gene products, individually or together, are requisite intermediaries of C5a/C5aR1‐initiated Mreg chemotaxis.…”

Section: Discussionmentioning

confidence: 99%

C5aR1 regulates migration of suppressive myeloid cells required for costimulatory blockade-induced murine allograft survival

Llaudo

Fribourg

Medof

et al. 2019

American Journal of Transplantation

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Costimulatory blockade-induced murine cardiac allograft survival requires intragraft accumulation of CD11b Ly6C Ly6G regulatory myeloid cells (Mregs) that expand regulatory T cells (Tregs) and suppress effector T cells (Teffs). We previously showed that C5a receptor (C5aR1) signaling on T cells activates Teffs and inhibits Tregs, but whether and/or how C5aR1 affects Mregs required for transplant survival is unknown. Although BALB/c hearts survived >60 days in anti-CD154 (MR1)-treated or cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig-treated wild-type (WT) recipients, they were rejected at ~30 days in MR1-treated or CTLA4-Ig-treated recipients selectively deficient in C5aR1 restricted to myeloid cells (C5ar1 xLysM-Cre). This accelerated rejection was associated with ~2-fold more donor-reactive T cells and ~40% less expansion of donor-reactive Tregs. Analysis of graft-infiltrating mononuclear cells on posttransplant day 6 revealed fewer Ly6C monocytes in C5ar1 xLysM-Cre recipients. Expression profiling of intragraft Ly6C monocytes showed that C5aR1 deficiency downregulated genes related to migration/locomotion without changes in genes associated with suppressive function. Cotransfer of C5ar1 and C5ar1 xLysM-Cre myeloid cells into MR1-treated allograft recipients resulted in less accumulation of C5ar1 cells within the allografts, and in vitro assays confirmed that Ly6C myeloid cells migrate to C5a/C5aR1-initiated signals. Together, our results newly link myeloid cell-expressed C5aR1 to intragraft accumulation of myeloid cells required for prolongation of heart transplant survival induced by costimulatory blockade.

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A reverse signaling pathway downstream of Sema4A controls cell migration via Scrib

Abstract: Semaphorins are ligands for their receptors, plexins. In this study, Sun et al. show that a transmembrane semaphorin, Sema4A, transduces signals in a reverse manner to control migration of cancer and dendritic cells via the cell polarity protein Scrib.

Cited by 42 publications

References 90 publications

Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation

Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation

Semaphorin Signaling in Cancer-Associated Inflammation

C5aR1 regulates migration of suppressive myeloid cells required for costimulatory blockade-induced murine allograft survival

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