PMID- 28674187
OWN - NLM
STAT- MEDLINE
DCOM- 20171003
LR  - 20181202
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 37
IP  - 19
DP  - 2017 Oct 1
TI  - PRAS40 Connects Microenvironmental Stress Signaling to Exosome-Mediated 
      Secretion.
LID - 10.1128/MCB.00171-17 [doi]
LID - e00171-17
AB  - Secreted exosomes carrying lipids, proteins, and nucleic acids conduct cell-cell 
      communications within the microenvironment of both physiological and pathological 
      conditions. Exosome secretion is triggered by extracellular or intracellular 
      stress signals. Little is known, however, about the signal transduction between 
      stress cues and exosome secretion. To identify the linker protein, we took 
      advantage of a unique finding in human keratinocytes. In these cells, although 
      transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) share 
      the same EGF receptor and previously indistinguishable intracellular signaling 
      networks, only TGF-alpha stimulation causes exosome-mediated secretion. However, 
      deduction of EGF-activated pathways from TGFalpha-activated pathways in the same 
      cells allowed us to identify the proline-rich Akt substrate of 40 kDa (PRAS40) as 
      the unique downstream effector of TGF-alpha but not EGF signaling via threonine 
      308-phosphorylated Akt. PRAS40 knockdown (KD) or PRAS40 dominant-negative (DN) 
      mutant overexpression blocks not only TGF-alpha- but also hypoxia- and 
      H(2)O(2)-induced exosome secretion in a variety of normal and tumor cells. 
      Site-directed mutagenesis and gene rescue studies show that Akt-mediated 
      activation of PRAS40 via threonine 246 phosphorylation is both necessary and 
      sufficient to cause exosome secretion without affecting the endoplasmic 
      reticulum/Golgi pathway. Identification of PRAS40 as a linker protein paves the 
      way for understanding how stress regulates exosome secretion under 
      pathophysiological conditions.
CI  - Copyright (c) 2017 American Society for Microbiology.
FAU - Guo, Jiacong
AU  - Guo J
AD  - Department of Dermatology and Norris Comprehensive Cancer Center, University of 
      Southern California Keck Medical Center, Los Angeles, California, USA.
FAU - Jayaprakash, Priyamvada
AU  - Jayaprakash P
AD  - Department of Dermatology and Norris Comprehensive Cancer Center, University of 
      Southern California Keck Medical Center, Los Angeles, California, USA.
FAU - Dan, Jian
AU  - Dan J
AD  - Department of Dermatology and Norris Comprehensive Cancer Center, University of 
      Southern California Keck Medical Center, Los Angeles, California, USA.
FAU - Wise, Petra
AU  - Wise P
AD  - Department of Pediatrics, Children's Center for Cancer and Blood Diseases and 
      Saban Research Institute, Children's Hospital Los Angeles, University of Southern 
      California Keck Medical Center, Los Angeles, California, USA.
FAU - Jang, Gyu-Beom
AU  - Jang GB
AD  - Department of Molecular Microbiology and Immunology, University of Southern 
      California Keck Medical Center, Los Angeles, California, USA.
FAU - Liang, Chengyu
AU  - Liang C
AD  - Department of Molecular Microbiology and Immunology, University of Southern 
      California Keck Medical Center, Los Angeles, California, USA.
FAU - Chen, Mei
AU  - Chen M
AD  - Department of Dermatology and Norris Comprehensive Cancer Center, University of 
      Southern California Keck Medical Center, Los Angeles, California, USA.
FAU - Woodley, David T
AU  - Woodley DT
AD  - Department of Dermatology and Norris Comprehensive Cancer Center, University of 
      Southern California Keck Medical Center, Los Angeles, California, USA.
FAU - Fabbri, Muller
AU  - Fabbri M
AD  - Department of Pediatrics, Children's Center for Cancer and Blood Diseases and 
      Saban Research Institute, Children's Hospital Los Angeles, University of Southern 
      California Keck Medical Center, Los Angeles, California, USA.
FAU - Li, Wei
AU  - Li W
AD  - Department of Dermatology and Norris Comprehensive Cancer Center, University of 
      Southern California Keck Medical Center, Los Angeles, California, USA 
      wli@usc.edu.
LA  - eng
GR  - R01 CA140964/CA/NCI NIH HHS/United States
GR  - R01 AR046538/AR/NIAMS NIH HHS/United States
GR  - R01 GM066193/GM/NIGMS NIH HHS/United States
GR  - R01 AR033625/AR/NIAMS NIH HHS/United States
GR  - R01 GM067100/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20170912
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (AKT1S1 protein, human)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (TGFA protein, human)
RN  - 0 (Transforming Growth Factor alpha)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*genetics/*metabolism
MH  - Animals
MH  - Cell Line, Tumor
MH  - Endoplasmic Reticulum/metabolism
MH  - Epidermal Growth Factor/pharmacology
MH  - ErbB Receptors/*metabolism
MH  - Exosomes/*metabolism
MH  - Humans
MH  - Keratinocytes/*cytology/drug effects/metabolism
MH  - Mice
MH  - Signal Transduction/drug effects
MH  - Stress, Physiological
MH  - Transforming Growth Factor alpha/*metabolism/pharmacology
PMC - PMC5599722
OTO - NOTNLM
OT  - Akt
OT  - HIF-1
OT  - HSP
OT  - exosome
OT  - growth factor
OT  - signal transduction
OT  - stress
EDAT- 2017/07/05 06:00
MHDA- 2017/10/04 06:00
PMCR- 2018/03/12
CRDT- 2017/07/05 06:00
PHST- 2017/04/09 00:00 [received]
PHST- 2017/06/15 00:00 [accepted]
PHST- 2017/07/05 06:00 [pubmed]
PHST- 2017/10/04 06:00 [medline]
PHST- 2017/07/05 06:00 [entrez]
PHST- 2018/03/12 00:00 [pmc-release]
AID - MCB.00171-17 [pii]
AID - 00171-17 [pii]
AID - 10.1128/MCB.00171-17 [doi]
PST - epublish
SO  - Mol Cell Biol. 2017 Sep 12;37(19):e00171-17. doi: 10.1128/MCB.00171-17. Print 
      2017 Oct 1.