m-calpain Activation Is Regulated by Its Membrane Localization and by Its Binding to Phosphatidylinositol 4,5-Bisphosphate* - Aix-Marseille Université Accéder directement au contenu
Article Dans Une Revue Journal of Biological Chemistry Année : 2010

m-calpain Activation Is Regulated by Its Membrane Localization and by Its Binding to Phosphatidylinositol 4,5-Bisphosphate*

Hanshuang Shao
  • Fonction : Auteur
Yong Ho Bae
  • Fonction : Auteur
Bridget Deasy
  • Fonction : Auteur
Donna Stolz
  • Fonction : Auteur
Partha Roy
  • Fonction : Auteur
Alan Wells
  • Fonction : Auteur

Résumé

m-calpain plays a critical role in cell migration enabling rear de-adhesion of adherent cells by cleaving structural components of the adhesion plaques. Growth factors and chemokines regulate keratinocyte, fibroblast, and endothelial cell migration by modulating m-calpain activity. Growth factor receptors activate m-calpain secondary to phosphorylation on serine 50 by ERK. Concurrently, activated m-calpain is localized to its inner membrane milieu by binding to phosphatidylinositol 4,5-bisphosphate (PIP2). Opposing this, CXCR3 ligands inhibit cell migration by blocking m-calpain activity secondary to a PKA-mediated phosphorylation in the C2-like domain. The failure of m-calpain activation in the absence of PIP2 points to a key regulatory role, although whether this PIP2-mediated membrane localization is regulatory for m-calpain activity or merely serves as a docking site for ERK phosphorylation is uncertain. Herein, we report the effects of two CXCR3 ligands, CXCL11/IP-9/I-TAC and CXCL10/IP-10, on the EGF- and VEGF-induced redistribution of m-calpain in human fibroblasts and endothelial cells. The two chemokines block the tail retraction and, thus, the migration within minutes, preventing and reverting growth factor-induced relocalization of m-calpain to the plasma membrane of the cells. PKA phosphorylation of m-calpain blocks the binding of the protease to PIP2. Unexpectedly, we found that this was due to membrane anchorage itself and not merely serine 50 phosphorylation, as the farnesylation-induced anchorage of m-calpain triggers a strong activation of this protease, leading notably to an increased cell death. Moreover, the ERK and PKA phosphorylations have no effect on this membrane-anchored m-calpain. However, the presence of PIP2 is still required for the activation of the anchored m-calpain. In conclusion, we describe a novel mechanism of m-calpain activation by interaction with the plasma membrane and PIP2 specifically, this phosphoinositide acting as a cofactor for the enzyme. The phosphorylation of m-calpain by ERK and PKA by growth factors and chemokines, respectively, act in cells to regulate the enzyme only indirectly by controlling its redistribution.

Dates et versions

hal-01740965 , version 1 (22-03-2018)

Identifiants

  • HAL Id : hal-01740965 , version 1
  • PUBMEDCENTRAL : PMC2963356

Citer

Ludovic Leloup, Hanshuang Shao, Yong Ho Bae, Bridget Deasy, Donna Stolz, et al.. m-calpain Activation Is Regulated by Its Membrane Localization and by Its Binding to Phosphatidylinositol 4,5-Bisphosphate*. Journal of Biological Chemistry, 2010, 285 (43). ⟨hal-01740965⟩
17 Consultations
0 Téléchargements

Partager

Gmail Facebook X LinkedIn More