Protéine d'adhésion cellulaire

Les protéines d'adhésion cellulaire (ou CAM, acronyme de l'anglais cell adhesion molecule, signifiant « molécule d'adhésion cellulaire ») sont des protéines intervenant dans les mécanismes de liaison cellulaire. Elles font partie de la superfamille des immunoglobulines. Structure Elles possèdent un domaine cytosolique (intracellulaire), un domaine transmembranaire et un domaine extracellulaire constitué de domaine C2 (constant) répétitifs reliés entre eux par des ponts disulfures. L'extrémité N-terminale située en extracellulaire, lie les protéoglycanes et les intégrines. Fonction Les CAM jouent un rôle dans l'interaction entre les leucocytes et les cellules endothéliale, entre les leucocytes et le tissu conjonctif ou encore entre les cellules endothéliales et le tissu conjonctif (important dans l'angiogenèse). Dans ce dernier cas 3 CAM joue un rôle important : les VCAM (Vascular CAM), les PECAM (Platelet CAM)et les ICAM (Intercellular CAM). Enfin il existe

Hippocampal neuroligin-2 links early-life stress with impaired social recognition and increased aggression in adult mice

Alexandre Claude Gustave Bacq, Céline Fournier, Jocelin Grosse, Maria del Carmen Sandi Perez

Early-life stress is a key risk factor for the development of neuropsychiatric disorders later in life. Neuronal cell adhesion molecules have been strongly implicated in the pathophysiology of psychiatric disorders and in modulating social behaviors associated with these diseases. Neuroligin-2 is a synaptic cell adhesion molecule, located at the postsynaptic membrane of inhibitory GABAergic synapses, and is involved in synaptic stabilization and maturation. Alterations in neuroligin-2 expression have previously been associated with changes in social behavior linked to psychiatric disorders, including schizophrenia and autism. In this study, we show that early-life stress, induced by limited nesting and bedding material, leads to impaired social recognition and increased aggression in adult mice, accompanied by increased expression levels of hippocampal neuroligin-2. Viral overexpression of hippocampal neuroligin-2 in adulthood mimics early-life stress-induced alterations in social behavior and social cognition. Moreover, viral knockdown of neuroligin-2 in the adult hippocampus attenuates the early-life stress-induced behavioral changes. Our results highlight the importance of neuroligin-2 in mediating early-life stress effects on social behavior and social cognition and its promising role as a novel therapeutic target for neuropsychiatric disorders.

2015

Role for MMP-9 in stress-induced downregulation of nectin-3 in hippocampal CA1 and associated behavioural alterations

Martina Fantin, Céline Fournier, Jocelin Grosse, Maria del Carmen Sandi Perez, Michael van der Kooij, Olivia Zanoletti

Chronic stress is a risk factor for the development of psychopathologies characterized by cognitive dysfunction and deregulated social behaviours. Emerging evidence suggests a role for cell adhesion molecules, including nectin-3, in the mechanisms that underlie the behavioural effects of stress. We tested the hypothesis that proteolytic processing of nectins by matrix metalloproteinases (MMPs), an enzyme family that degrades numerous substrates, including cell adhesion molecules, is involved in hippocampal effects induced by chronic restraint stress. A reduction in nectin-3 in the perisynaptic CA1, but not in the CA3, compartment is observed following chronic stress and is implicated in the effects of stress in social exploration, social recognition and a CA1-dependent cognitive task. Increased MMP-9-related gelatinase activity, involving N-methyl-D-aspartate receptor, is specifically found in the CA1 and involved in nectin-3 cleavage and chronic stress-induced social and cognitive alterations. Thus, MMP-9 proteolytic processing emerges as an important mediator of stress effects in brain function and behaviour.

2014

Novel compartment-specific biosensors reveal a complementary subcellular distribution of bioactive Furin and PC7

Pierpaolo Ginefra

Proprotein Convertases (PCs) constitute a family of serine proteases that activate various hormones, growth factors and cell adhesion molecules by mediating endoproteolytic cleavage of their secreted inactive precursors during their transit in the secretory pathway. Their physiological roles in most tissues, in cancer and other diseases have remained nowadays poorly defined, partly because of technical hurdles in clearly distinguishing functionally overlapping PC activities from each other. Related to this, a major unsolved question is where, among the different subcellular compartments of the secretory pathway, substrate cleavage takes place. To address these questions, we mapped intracellular PC activities of two unrelated cell lines (HEK293T and B16F1 melanoma) by ratiometric and Förster Resonance Energy Transfer (FRET)-based imaging of the PC-specific biosensors, called cell-linked indicator of proteolysis (CLIP)v3 and CLIPv4 respectively, which are sorted to different subcellular compartments by specific trafficking signals. Until now, PCs have been thought to cleave the majority of the substrates in the trans-Golgi network (TGN). By contrast, our analysis of compartment-specific CLIPv3 and CLIPv4 variants in cultured cells suggested that PC activities are much higher in post-exocytic compartments. Furthermore, imaging in B16F1 Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-edited clones for endogenously expressed Furin or PC7, revealed an enrichment of Furin activity in endosomes compared to TGN, whereas PC7 activity was confined to a distinct compartment resistant to the pan-PC inhibitor CMK, demonstrating that endogenous Furin and PC7 are biologically active in distinct compartments. In addition, we also demonstrated that substrate and protease localization are rate-limiting of how efficiently a given substrate is processed. PC inhibition represses human primary melanoma cells motility and migration in vitro and proliferation in other skin cancer cells both in vitro and in vivo. To elucidate the roles of PC activities in melanoma progression and differentiation, we evaluated relative contribution of Furin and PC7 in B16F1 tumor grafts. Both proteins were required for tumor pigmentation, whereas Furin deletion reduced tumor growth, but its loss may be rescued by PC7 deletion. Altogether, these findings will be important to inform future therapeutic approaches and strategies for targeting PCs to preferentially block oncogenic activities.

EPFL2018

Novel compartment-specific biosensors reveal a complementary subcellular distribution of bioactive Furin and PC7

Pierpaolo Ginefra

EPFL2018

Protéine d'adhésion cellulaire

Hippocampal neuroligin-2 links early-life stress with impaired social recognition and increased aggression in adult mice

Role for ​MMP-9 in stress-induced downregulation of ​nectin-3 in hippocampal CA1 and associated behavioural alterations

Novel compartment-specific biosensors reveal a complementary subcellular distribution of bioactive Furin and PC7

Role for ​MMP-9 in stress-induced downregulation of ​nectin-3 in hippocampal CA1 and associated behavioural alterations

Novel compartment-specific biosensors reveal a complementary subcellular distribution of bioactive Furin and PC7

Hippocampal neuroligin-2 links early-life stress with impaired social recognition and increased aggression in adult mice

Role for MMP-9 in stress-induced downregulation of nectin-3 in hippocampal CA1 and associated behavioural alterations

Role for MMP-9 in stress-induced downregulation of nectin-3 in hippocampal CA1 and associated behavioural alterations