SOAP: Signaling in Oncogenesis, Angiogenesis, and Permeability
On the ground of our interests for molecular piracy exerted by tumor cells to survive, adapt and remodel their environment, we explore the signaling mechanisms involved in non-oncogene addiction and loss of vascular homeostasis.
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SHARPIN is Phosphorylated!
Thys et al., IScience 2020
GP130 is a cicerone for APLNR
Trillet et al., J Cell Biol 2021
Research Highlights
The glycoprotein GP130 governs the surface presentation of the G protein–coupled receptor APLNR.
Kilian Trillet, Kathryn A Jacobs, Gwennan André-Grégoire, An Thys, Clément Maghe, Jonathan Cruard, Stéphane Minvielle, Sara Gonzalez Diest, Guillaume Montagnac, Nicolas Bidère, Julie Gavard.
J Cell Biol 2021
Glioblastoma is one of the most lethal forms of adult cancer, with a median survival of ∼15 mo. Targeting glioblastoma stem-like cells (GSCs) at the origin of tumor formation and relapse may prove beneficial. In situ, GSCs are nested within the vascular bed in tight interaction with brain endothelial cells, which positively control their expansion. Because GSCs are notably addicted to apelin (APLN), sourced from the surrounding endothelial stroma, the APLN/APLNR nexus has emerged as a druggable network. However, how this signaling axis operates in gliomagenesis remains underestimated. Here, we find that the glycoprotein GP130 interacts with APLNR at the plasma membrane of GSCs and arbitrates its availability at the surface via ELMOD1, which may further impact on ARF-mediated endovesicular trafficking. From a functional standpoint, interfering with GP130 thwarts APLNR-mediated self-renewal of GSCs ex vivo. Thus, GP130 emerges as an unexpected cicerone to the G protein-coupled APLN receptor, opening new therapeutic perspectives toward the targeting of cancer stem cells.
Serine 165 Phosphorylation of SHARPIN regulates the Activation of NF-κB.
Thys A, Trillet K, Rosinska S, Gayraud A, Douanne T, Danger Y, Renaud CCN, Antigny L, Lavigne R, Pineau C, Com E, Vérité F, Gavard J, Bidère N.
IScience 2020
The adaptor SHARPIN composes, together with the E3 ligases HOIP and HOIL1, the linear ubiquitin chain assembly complex (LUBAC). This enzymatic complex catalyzes and stamps atypical linear ubiquitin chains onto substrates to modify their fate, and has been linked to the regulation of the NF-κB pathway downstream most immunoreceptors, inflammation and cell death. However, how this signaling complex is regulated is not fully understood. Here, we report that a portion of SHARPIN is constitutively phosphorylated on the serine in position 165 in lymphoblastoid cells, and can be further induced following T-cell receptor stimulation. Analysis of a phosphorylation-resistant mutant of SHARPIN revealed that this mark controls the linear ubiquitination of the NF-κB regulator NEMO, and allows the optimal activation of NF-κB in response to TNFα. These results identify an additional layer of regulation of the LUBAC, and unveil potential strategies to modulate its action.
Funding
Canceropole GO
CNRS
Fondation ARC
Fondation de France
Fondation pour la Recherche Médicale
Institut National du Cancer
Inserm
Ligue Nationale et Régionale contre le Cancer
