Seminar: Eric Rubinstein

Tetraspanins regulate the metalloprotease ADAM10 through membrane compartmentalization. Implications for Notch signaling.

Date:
21 September 2016 16:00 hrs. - 17:00 hrs.
Location:
Location see remarks
Title:
Tetraspanins regulate the metalloprotease ADAM10 through membrane compartmentalization. Implications for Notch signaling
Speaker(s):

Eric Rubinstein, Inserm, Universite Paris-Sud, France

Host(s):

Annemiek van Spriel, Dept. of Tumor Immunology, RIMLS

21-09-2016 16:00:0021-09-2016 17:00:00Europe/AmsterdamTetraspanins regulate the metalloprotease ADAM10 through membrane compartmentalization. Implications for Notch signaling Location see remarksRimlsrimls@radboudumc.nl

Remarks / more information:


Location: Knowledge Square 5th floor RIMLS building, route 274

undefined
undefinedADAM10 is a member of the ADAM (A Disintegrin and Metalloprotease) family of membrane-anchored zinc metalloproteases . Acting in the juxtamembrane region, the ADAM proteases are responsible for the ectodomain shedding of various membrane-anchored proteins. ADAM10 is a major candidate for the alpha-secretase cleavage of APP, the membrane anchored precursor of the amyloid-beta peptide (Ab), a major component of amyloid plaques associated with Alzheimer's disease. Another key substrate of ADAM10 is the transmembrane receptor Notch. The binding of Notch to its ligands is followed by ADAM10 or ADAM17-dependent cleavage, allowing a second proteolytic cleavage in the transmembrane region mediated by the g-secretase complex. This results in the release of the intracellular domain of Notch that acts as a transcriptional co-activator of CSL to regulate the expression of Notch target genes.

Tetraspanins are proteins with 4 transmembrane domains that play a key role in many physiological processes including reproduction, vision, immunity, kidney function, muscle regeneration and mental capacity. Their function is linked at least in part to their ability organize a hierarchical dynamic network of interaction at the cell surface. We have recently identified a set of 6 mammalian tetraspanins, collectively referred to as TspanC8 (C8 because they have 8 cysteines in their large extracellular domain) that directly interact with ADAM10. These TspanC8 tetraspanins are key regulators of ADAM10 trafficking, controlling ADAM10 exit from the endoplasmic reticulum (ER), and targeting it to either late endosomes or the plasma membrane. At the plasma membrane, the different TspanC8 tetraspanins differentially regulate ADAM10 substrate selectivity, and Notch signaling, with Tspan5 and Tspan14 being positive regulators of this pathway, and Tspan15 a negative regulator. This is associated with a change in ADAM10 membrane compartmentalization, highlighting the key role of this level of regulation for cell signaling.

Flyer



<< back to all events