title: Presenilin-dependent intramembrane cleavage of ephrin-B1.
abstract: BACKGROUND
  Presenilin-dependent gamma-secretase cleavage of several transmembrane proteins, including amyloid-beta precursor protein and Notch, mediates the intramembrane proteolysis to liberate their intracellular domains that are involved in cellular signaling. Considering gamma-secretase inhibitors as therapeutics for Alzheimer's disease, understanding the physiologically and biologically important substrate for gamma-secretase activity in brains is emerging issue. To elucidate the molecular mechanism and physiological role of gamma-secretase, we screened candidate molecules for gamma-secretase substrates.
  
  
  RESULTS
  We show that ephrin-B1, that participates in cell-cell repulsive and attractive signaling together with its Eph receptor, constitutively undergoes ectodomain shedding and that the residual membrane-tethered fragment is sequentially cleaved by gamma-secretase to release the intracellular domain. Furthermore, overexpression of membrane-tethered ephrin-B1 caused protrusion of numerous cellular processes consisted of F-actin, that required the preservation of the most C-terminal region of ephrin-B1. In contrast, soluble intracellular domain translocated into the nucleus and had no effect on cell morphology.
  
  
  CONCLUSIONS
  Our findings suggest that ephrin-B is a genuine substrate for gamma-secretase and regulates the cytoskeletal dynamics through intramembrane proteolysis.
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. taisuke@mol.f.u-tokyo.ac.jp
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Sayaka
authors.initials: S
authors.lastname: Tanaka
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Morohashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo