PMID- 22991200
OWN - NLM
STAT- MEDLINE
DCOM- 20130128
LR  - 20230619
IS  - 1949-3592 (Electronic)
IS  - 1949-3584 (Print)
IS  - 1949-3592 (Linking)
VI  - 69
IP  - 9
DP  - 2012 Sep
TI  - Regulation of late endosomal/lysosomal maturation and trafficking by cortactin 
      affects Golgi morphology.
PG  - 625-43
LID - 10.1002/cm.21051 [doi]
AB  - Cortactin is a branched actin regulator and tumor-overexpressed protein that 
      promotes vesicular trafficking at a variety of cellular sites, including 
      endosomes and the trans-Golgi network. To better understand its role in secretory 
      trafficking, we investigated its function in Golgi homeostasis. Here, we report 
      that knockdown (KD) of cortactin leads to a dramatic change in Golgi morphology 
      by light microscopy, dependent on binding the Arp2/3 actin-nucleating complex. 
      Surprisingly, there was little effect of cortactin-KD on anterograde trafficking 
      of the constitutive cargo vesicular stomatitis virus glycoprotein (VSVG), Golgi 
      assembly from endoplasmic reticulum membranes upon Brefeldin A washout, or Golgi 
      ultrastructure. Instead, electron microscopy studies revealed that cortactin-KD 
      cells contained a large number of immature-appearing late endosomal/lysosomal 
      (LE/Lys) hybrid organelles, similar to those found in lysosomal storage diseases. 
      Consistent with a defect in LE/Lys trafficking, cortactin-KD cells also exhibited 
      accumulation of free cholesterol and retention of the retrograde Golgi cargo 
      mannose-6-phosphate receptor in LE. Inhibition of LE maturation by treatment of 
      control cells with Rab7 siRNA or chloroquine led to a compact Golgi morphology 
      similar to that observed in cortactin-KD cells. Furthermore, the Golgi morphology 
      defects of cortactin-KD cells could be rescued by removal of 
      cholesterol-containing lipids from the media, suggesting that buildup of 
      cholesterol-rich membranes in immature LE/Lys induced disturbances in retrograde 
      trafficking. Taken together, these data reveal that LE/Lys maturation and 
      trafficking are highly sensitive to cortactin-regulated branched actin assembly 
      and suggests that cytoskeletal-induced Golgi morphology changes can be a 
      consequence of altered trafficking at late endosomes.
CI  - 2012 Wiley Periodicals, Inc
FAU - Kirkbride, Kellye C
AU  - Kirkbride KC
AD  - Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, 
      Tennessee 37232, USA.
FAU - Hong, Nan Hyung
AU  - Hong NH
FAU - French, Christi L
AU  - French CL
FAU - Clark, Emily S
AU  - Clark ES
FAU - Jerome, W Gray
AU  - Jerome WG
FAU - Weaver, Alissa M
AU  - Weaver AM
LA  - eng
GR  - 5T32 CA009592-23/CA/NCI NIH HHS/United States
GR  - DK58404/DK/NIDDK NIH HHS/United States
GR  - P30 DK058404/DK/NIDDK NIH HHS/United States
GR  - EY08126/EY/NEI NIH HHS/United States
GR  - P30 EY008126/EY/NEI NIH HHS/United States
GR  - F31 DE021619/DE/NIDCR NIH HHS/United States
GR  - 1R01GM075126/GM/NIGMS NIH HHS/United States
GR  - DK20593/DK/NIDDK NIH HHS/United States
GR  - R21 DE018244/DE/NIDCR NIH HHS/United States
GR  - TL1 RR024978/RR/NCRR NIH HHS/United States
GR  - P30 HD015052/HD/NICHD NIH HHS/United States
GR  - KL2 RR024977/RR/NCRR NIH HHS/United States
GR  - DK59637/DK/NIDDK NIH HHS/United States
GR  - P30 DK020593/DK/NIDDK NIH HHS/United States
GR  - P30 CA068485/CA/NCI NIH HHS/United States
GR  - T32 CA009592/CA/NCI NIH HHS/United States
GR  - CA68485/CA/NCI NIH HHS/United States
GR  - R01 GM075126/GM/NIGMS NIH HHS/United States
GR  - UL1 RR024975/RR/NCRR NIH HHS/United States
GR  - HD15052/HD/NICHD NIH HHS/United States
GR  - 1R21DE018244/DE/NIDCR NIH HHS/United States
GR  - 1F31DE021619/DE/NIDCR NIH HHS/United States
GR  - U24 DK059637/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120731
PL  - United States
TA  - Cytoskeleton (Hoboken)
JT  - Cytoskeleton (Hoboken, N.J.)
JID - 101523844
RN  - 0 (Actins)
RN  - 0 (Cortactin)
SB  - IM
MH  - Actins/*metabolism
MH  - Cell Line, Tumor
MH  - Cortactin/genetics/*metabolism
MH  - Endosomes/*metabolism
MH  - Golgi Apparatus/*metabolism
MH  - Humans
MH  - Lysosomes/*metabolism
MH  - Microscopy, Confocal
MH  - Microscopy, Electron, Transmission
PMC - PMC3746372
MID - NIHMS498593
COIS- The authors have no conflict of interest to declare.
EDAT- 2012/09/20 06:00
MHDA- 2013/01/29 06:00
PMCR- 2013/09/01
CRDT- 2012/09/20 06:00
PHST- 2012/06/22 00:00 [received]
PHST- 2012/07/11 00:00 [revised]
PHST- 2012/07/11 00:00 [accepted]
PHST- 2012/09/20 06:00 [entrez]
PHST- 2012/09/20 06:00 [pubmed]
PHST- 2013/01/29 06:00 [medline]
PHST- 2013/09/01 00:00 [pmc-release]
AID - 10.1002/cm.21051 [doi]
PST - ppublish
SO  - Cytoskeleton (Hoboken). 2012 Sep;69(9):625-43. doi: 10.1002/cm.21051. Epub 2012 
      Jul 31.