Phosphoprotein enriched in astrocytes (PEA)-15: A potential therapeutic target in multiple disease states

Fiona H Greig, Graeme F Nixon

Research output: Contribution to journalArticle

14 Citations (Scopus)
6 Downloads (Pure)

Abstract

Phosphoprotein enriched in astrocytes-15 (PEA-15) is a cytoplasmic protein that sits at an important junction in intracellular signalling and can regulate diverse cellular processes, such as proliferation and apoptosis, dependent upon stimulation. Regulation of these processes occurs by virtue of the unique interaction of PEA-15 with other signalling proteins. PEA-15 acts as a cytoplasmic tether for the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) preventing nuclear localisation. In order to release ERK1/2, PEA-15 requires to be phosphorylated via several potential pathways. PEA-15 (and its phosphorylation state) therefore regulates many ERK1/2-dependent processes, including proliferation, via regulating ERK1/2 nuclear translocation. In addition, PEA-15 contains a death effector domain (DED) which allows interaction with other DED-containing proteins. PEA-15 can bind the DED-containing apoptotic adaptor molecule, Fas-associated death domain protein (FADD) which is also dependent on the phosphorylation status of PEA-15. PEA-15 binding of FADD can inhibit apoptosis as bound FADD cannot participate in the assembly of apoptotic signalling complexes. Through these protein-protein interactions, PEA-15-regulated cellular effects have now been investigated in a number of disease-related studies. Changes in PEA-15 expression and regulation have been observed in diabetes mellitus, cancer, neurological disorders and the cardiovascular system. These changes have been suggested to contribute to the pathology related to each of these disease states. As such, new therapeutic targets based around PEA-15 and its associated interactions are now being uncovered and could provide novel avenues for treatment strategies in multiple diseases.
Original languageEnglish
Pages (from-to)265-274
Number of pages10
JournalPharmacology & Therapeutics
Volume143
Issue number3
Early online date20 Mar 2014
DOIs
Publication statusPublished - Sep 2014

Fingerprint

Phosphoproteins
Astrocytes
Fas-Associated Death Domain Protein
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Therapeutics
Proteins
Death Domain Receptor Signaling Adaptor Proteins
Phosphorylation
Apoptosis
Cardiovascular System
Mitogen-Activated Protein Kinases
Nervous System Diseases
Diabetes Mellitus
Pathology

Keywords

  • PEA-15
  • ERK1/2
  • proliferation
  • apoptosis
  • cancer
  • type 2 diabetes

Cite this

Phosphoprotein enriched in astrocytes (PEA)-15 : A potential therapeutic target in multiple disease states. / Greig, Fiona H; Nixon, Graeme F.

In: Pharmacology & Therapeutics, Vol. 143, No. 3, 09.2014, p. 265-274.

Research output: Contribution to journalArticle

@article{c95421618b7448c78710554c583934a2,
title = "Phosphoprotein enriched in astrocytes (PEA)-15: A potential therapeutic target in multiple disease states",
abstract = "Phosphoprotein enriched in astrocytes-15 (PEA-15) is a cytoplasmic protein that sits at an important junction in intracellular signalling and can regulate diverse cellular processes, such as proliferation and apoptosis, dependent upon stimulation. Regulation of these processes occurs by virtue of the unique interaction of PEA-15 with other signalling proteins. PEA-15 acts as a cytoplasmic tether for the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) preventing nuclear localisation. In order to release ERK1/2, PEA-15 requires to be phosphorylated via several potential pathways. PEA-15 (and its phosphorylation state) therefore regulates many ERK1/2-dependent processes, including proliferation, via regulating ERK1/2 nuclear translocation. In addition, PEA-15 contains a death effector domain (DED) which allows interaction with other DED-containing proteins. PEA-15 can bind the DED-containing apoptotic adaptor molecule, Fas-associated death domain protein (FADD) which is also dependent on the phosphorylation status of PEA-15. PEA-15 binding of FADD can inhibit apoptosis as bound FADD cannot participate in the assembly of apoptotic signalling complexes. Through these protein-protein interactions, PEA-15-regulated cellular effects have now been investigated in a number of disease-related studies. Changes in PEA-15 expression and regulation have been observed in diabetes mellitus, cancer, neurological disorders and the cardiovascular system. These changes have been suggested to contribute to the pathology related to each of these disease states. As such, new therapeutic targets based around PEA-15 and its associated interactions are now being uncovered and could provide novel avenues for treatment strategies in multiple diseases.",
keywords = "PEA-15, ERK1/2, proliferation, apoptosis, cancer, type 2 diabetes",
author = "Greig, {Fiona H} and Nixon, {Graeme F}",
note = "Copyright {\circledC} 2014 Elsevier Inc. All rights reserved.",
year = "2014",
month = "9",
doi = "10.1016/j.pharmthera.2014.03.006",
language = "English",
volume = "143",
pages = "265--274",
journal = "Pharmacology & Therapeutics",
issn = "0163-7258",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - Phosphoprotein enriched in astrocytes (PEA)-15

T2 - A potential therapeutic target in multiple disease states

AU - Greig, Fiona H

AU - Nixon, Graeme F

N1 - Copyright © 2014 Elsevier Inc. All rights reserved.

PY - 2014/9

Y1 - 2014/9

N2 - Phosphoprotein enriched in astrocytes-15 (PEA-15) is a cytoplasmic protein that sits at an important junction in intracellular signalling and can regulate diverse cellular processes, such as proliferation and apoptosis, dependent upon stimulation. Regulation of these processes occurs by virtue of the unique interaction of PEA-15 with other signalling proteins. PEA-15 acts as a cytoplasmic tether for the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) preventing nuclear localisation. In order to release ERK1/2, PEA-15 requires to be phosphorylated via several potential pathways. PEA-15 (and its phosphorylation state) therefore regulates many ERK1/2-dependent processes, including proliferation, via regulating ERK1/2 nuclear translocation. In addition, PEA-15 contains a death effector domain (DED) which allows interaction with other DED-containing proteins. PEA-15 can bind the DED-containing apoptotic adaptor molecule, Fas-associated death domain protein (FADD) which is also dependent on the phosphorylation status of PEA-15. PEA-15 binding of FADD can inhibit apoptosis as bound FADD cannot participate in the assembly of apoptotic signalling complexes. Through these protein-protein interactions, PEA-15-regulated cellular effects have now been investigated in a number of disease-related studies. Changes in PEA-15 expression and regulation have been observed in diabetes mellitus, cancer, neurological disorders and the cardiovascular system. These changes have been suggested to contribute to the pathology related to each of these disease states. As such, new therapeutic targets based around PEA-15 and its associated interactions are now being uncovered and could provide novel avenues for treatment strategies in multiple diseases.

AB - Phosphoprotein enriched in astrocytes-15 (PEA-15) is a cytoplasmic protein that sits at an important junction in intracellular signalling and can regulate diverse cellular processes, such as proliferation and apoptosis, dependent upon stimulation. Regulation of these processes occurs by virtue of the unique interaction of PEA-15 with other signalling proteins. PEA-15 acts as a cytoplasmic tether for the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) preventing nuclear localisation. In order to release ERK1/2, PEA-15 requires to be phosphorylated via several potential pathways. PEA-15 (and its phosphorylation state) therefore regulates many ERK1/2-dependent processes, including proliferation, via regulating ERK1/2 nuclear translocation. In addition, PEA-15 contains a death effector domain (DED) which allows interaction with other DED-containing proteins. PEA-15 can bind the DED-containing apoptotic adaptor molecule, Fas-associated death domain protein (FADD) which is also dependent on the phosphorylation status of PEA-15. PEA-15 binding of FADD can inhibit apoptosis as bound FADD cannot participate in the assembly of apoptotic signalling complexes. Through these protein-protein interactions, PEA-15-regulated cellular effects have now been investigated in a number of disease-related studies. Changes in PEA-15 expression and regulation have been observed in diabetes mellitus, cancer, neurological disorders and the cardiovascular system. These changes have been suggested to contribute to the pathology related to each of these disease states. As such, new therapeutic targets based around PEA-15 and its associated interactions are now being uncovered and could provide novel avenues for treatment strategies in multiple diseases.

KW - PEA-15

KW - ERK1/2

KW - proliferation

KW - apoptosis

KW - cancer

KW - type 2 diabetes

U2 - 10.1016/j.pharmthera.2014.03.006

DO - 10.1016/j.pharmthera.2014.03.006

M3 - Article

C2 - 24657708

VL - 143

SP - 265

EP - 274

JO - Pharmacology & Therapeutics

JF - Pharmacology & Therapeutics

SN - 0163-7258

IS - 3

ER -