PMID- 29899118
OWN - NLM
STAT- MEDLINE
DCOM- 20190204
LR  - 20210317
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 293
IP  - 29
DP  - 2018 Jul 20
TI  - Endocytosis is required for CXC chemokine receptor type 4 (CXCR4)-mediated Akt 
      activation and antiapoptotic signaling.
PG  - 11470-11480
LID - S0021-9258(20)31569-6 [pii]
LID - 10.1074/jbc.RA118.001872 [doi]
AB  - Signaling activated by binding of the CXC motif chemokine ligand 12 (CXCL12) to 
      its cognate G protein-coupled receptor (GPCR), chemokine CXC motif receptor 4 
      (CXCR4), is linked to metastatic disease. However, the mechanisms governing CXCR4 
      signaling remain poorly understood. Here, we show that endocytosis and early 
      endosome antigen 1 (EEA1), which is part of the endosome fusion machinery, are 
      required for CXCL12-mediated AKT Ser/Thr kinase (Akt) signaling selective for 
      certain Akt substrates. Pharmacological inhibition of endocytosis partially 
      attenuated CXCL12-induced phosphorylation of Akt, but not phosphorylation of 
      ERK-1/2. Similarly, phosphorylation of Akt, but not ERK-1/2, stimulated by 
      CXCL13, the cognate ligand for the chemokine receptor CXCR5, was also attenuated 
      by inhibited endocytosis. Furthermore, siRNA-mediated depletion of the 
      Rab5-effector EEA1, but not of adaptor protein, phosphotyrosine-interacting with 
      PH domain and leucine zipper 1 (APPL1), partially attenuated Akt, but not 
      ERK-1/2, phosphorylation promoted by CXCR4. Attenuation of Akt phosphorylation 
      through inhibition of endocytosis or EEA1 depletion was associated with reduced 
      signaling to Akt substrate forkhead box O1/3a but not the Akt substrates TSC 
      complex subunit 2 or glycogen synthase kinase 3beta. This suggested that endocytosis 
      and endosomes govern discrete aspects of CXCR4- or CXCR5-mediated Akt signaling. 
      Consistent with this hypothesis, depletion of EEA1 reduced the ability of CXCL12 
      to attenuate apoptosis in suspended, but not adherent, HeLa cells. Our results 
      suggest a mechanism whereby compartmentalized chemokine-mediated Akt signaling 
      from endosomes suppresses the cancer-related process known as anoikis. Targeting 
      this signaling pathway may help inhibit metastatic cancer involving receptors 
      such as CXCR4.
CI  - (c) 2018 English et al.
FAU - English, Elizabeth J
AU  - English EJ
AD  - Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 
      53226.
FAU - Mahn, Sarah A
AU  - Mahn SA
AD  - Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 
      53226.
FAU - Marchese, Adriano
AU  - Marchese A
AD  - Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 
      53226. Electronic address: amarchese@mcw.edu.
LA  - eng
GR  - R01 GM106727/GM/NIGMS NIH HHS/United States
GR  - R01 GM122889/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180613
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Receptors, CXCR4)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - *Apoptosis
MH  - *Endocytosis
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - HeLa Cells
MH  - Humans
MH  - MAP Kinase Signaling System
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Receptors, CXCR4/*metabolism
MH  - *Signal Transduction
PMC - PMC6065176
OTO - NOTNLM
OT  - Akt PKB
OT  - C-X-C chemokine receptor type 4 (CXCR-4)
OT  - FOXO
OT  - G protein-coupled receptor (GPCR)
OT  - anoikis
OT  - apoptosis
OT  - chemokine
OT  - endocytosis
OT  - endosome
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2018/06/15 06:00
MHDA- 2019/02/05 06:00
PMCR- 2019/07/20
CRDT- 2018/06/15 06:00
PHST- 2018/01/15 00:00 [received]
PHST- 2018/06/07 00:00 [revised]
PHST- 2018/06/15 06:00 [pubmed]
PHST- 2019/02/05 06:00 [medline]
PHST- 2018/06/15 06:00 [entrez]
PHST- 2019/07/20 00:00 [pmc-release]
AID - S0021-9258(20)31569-6 [pii]
AID - RA118.001872 [pii]
AID - 10.1074/jbc.RA118.001872 [doi]
PST - ppublish
SO  - J Biol Chem. 2018 Jul 20;293(29):11470-11480. doi: 10.1074/jbc.RA118.001872. Epub 
      2018 Jun 13.