PED/PEA‐15 interacts with the 67 kD laminin receptor and regulates cell adhesion, migration, proliferation and apoptosis

Abstract

Phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes-15 kD (PED/PEA-15) is an anti-apoptotic protein whose expression is increased in several human cancers. In addition to apoptosis, PED/PEA-15 is involved in the regulation of other major cellular functions, including cell adhesion, migration, proliferation and glucose metabolism. To further understand the functions of this protein, we performed a yeast two-hybrid screening using PED/PEA-15 as a bait and identified the 67 kD high-affinity laminin receptor (67LR) as an interacting partner. 67 kD laminin receptor is a non-integrin cell-surface receptor for the extracellular matrix (ECM), derived from the dimerization of a 37 kD cytosolic precursor (37LRP). The 67LR is highly expressed in human cancers and widely recognized as a molecular marker of metastatic aggressiveness. The molecular interaction of PED/PEA-15 with 67LR was confirmed by pull-down experiments with recombinant His-tagged 37LRP on lysates of PED/PEA-15 transfected HEK-293 cells. Further, overexpressed or endogenous PED/PEA-15 was co-immunoprecipitated with 67LR in PED/PEA-15-transfected HEK-293 cells and in U-373 glioblastoma cells, respectively. PED/PEA-15 overexpression significantly increased 67LR-mediated HEK-293 cell adhesion and migration to laminin that, in turn, determined PED/PEA-15 phosphorylation both in Ser-104 and Ser-116, thus enabling cell proliferation and resistance to apoptosis. PED/PEA-15 ability to induce cell responses to ECM-derived signals through interaction with 67LR may be of crucial importance for tumour cell survival in a poor microenvironment, thus favouring the metastatic spread and colonization.

Overexpression of PrPc, combined with MGr1‐Ag/37LRP, is predictive of poor prognosis in gastric cancer

“…Further studies suggested that MGr1‐Ag/37LRP could promote MDR of GC cells via enhancing cell adhesion and then inhibiting drug‐induced apoptosis . Several studies indicated that 37LRP was involved in tumor development and progression . Moreover, an interaction between 37LRP and PrPc was first established in a two‐hybrid screening of a HeLa cDNA expression library for PrPc‐interacting proteins .…”

“…[15][16][17] Several studies indicated that 37LRP was involved in tumor development and progression. [18][19][20] Moreover, an interaction between 37LRP and PrPc was first established in a two-hybrid screening of a HeLa cDNA expression library for PrPc-interacting proteins. 22,36,37 The pathogenic relevance of 37LRP/67LR and PrPc interaction was revealed in tissues and cells of scrapie compared with nonscrapie-infected mice.…”

“…Forced expression of MGr1‐Ag/37LRP in GC cells could increase drug resistance toward a variety of chemotherapy drugs . Previous studies demonstrated that 37LRP was involved in tumor development and progression . Moreover, it has been shown that 37LRP acts as a receptor for PrPsc, as well as a receptor or coreceptor for PrPc in prion disease .…”

“…[15][16][17] Previous studies demonstrated that 37LRP was involved in tumor development and progression. [18][19][20] Moreover, it has been shown that 37LRP acts as a receptor for PrPsc, as well as a receptor or coreceptor for PrPc in prion disease. 21,22 PrPc is co-localized with 37LRP on the surface of mammalian cells.…”

Reactive astrocytes associated with plaques in TgCRND8 mouse brain and in human Alzheimer brain express phosphoprotein enriched in astrocytes (PEA‐15)

“…The N-terminal DED in PEA-15 has led to investigations into its role in regulating apoptosis [9,10,12]. More recently it has been discovered that PEA-15 has a diverse set of regulatory functions, including roles in proliferation, glucose metabolism, cell cycle control, cell adhesion, migration and autophagy and its expression has been shown to be altered in various cancers [9,10,[12][13][14].…”