PMID- 18728784
OWN - NLM
STAT- MEDLINE
DCOM- 20081218
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 3
IP  - 8
DP  - 2008 Aug 27
TI  - Synthetic activation of endogenous PI3K and Rac identifies an AND-gate switch for 
      cell polarization and migration.
PG  - e3068
LID - 10.1371/journal.pone.0003068 [doi]
LID - e3068
AB  - Phosphatidylinositol 3-OH kinase (PI3K) has been widely studied as a principal 
      regulator of cell polarization, migration, and chemotaxis. Surprisingly, recent 
      studies showed that mammalian neutrophils and Dictyostelium discoideum cells can 
      polarize and migrate in the absence of PI3K activity. Here we directly probe the 
      roles of PI3K and its downstream effector, Rac, in HL-60 neutrophils by using a 
      chemical biology approach whereby the endogenously present enzymes are 
      synthetically activated in less than one minute. We show that uniform activation 
      of endogenous PI3K is sufficient to polarize previously unpolarized neutrophils 
      and trigger effective cell migration. After a delay following symmetrical 
      phosphatidylinositol (3,4,5)-triphosphate (PIP(3)) production, a polarized 
      distribution of PIP(3) was induced by positive feedback requiring actin 
      polymerization. Pharmacological studies argue that this process does not require 
      receptor-coupled trimeric G proteins. Contrary to the current working model, 
      rapid activation of endogenous Rac proteins triggered effective actin 
      polymerization but failed to feed back to PI3K to generate PIP(3) or induce cell 
      polarization. Thus, the increase in PIP(3) concentration at the leading edge is 
      generated by positive feedback with an AND gate logic with a PI3K-Rac-actin 
      polymerization pathway as a first input and a PI3K initiated non-Rac pathway as a 
      second input. This AND-gate control for cell polarization can explain how Rac can 
      be employed for both PI3K-dependent and -independent signaling pathways 
      coexisting in the same cell.
FAU - Inoue, Takanari
AU  - Inoue T
AD  - Chemical and Systems Biology, Bio-X Program, Stanford University, Stanford, 
      California, USA.
FAU - Meyer, Tobias
AU  - Meyer T
LA  - eng
GR  - R01 GM063702/GM/NIGMS NIH HHS/United States
GR  - PN2 EY1018241/EY/NEI NIH HHS/United States
GR  - GM063702/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080827
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Actins)
RN  - 0 (Bacterial Proteins)
RN  - 0 (Luminescent Proteins)
RN  - 0 (yellow fluorescent protein, Bacteria)
RN  - 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
SB  - IM
MH  - Actins/metabolism
MH  - Bacterial Proteins/genetics
MH  - Cell Movement/physiology
MH  - Cell Polarity/physiology
MH  - Chemotaxis/physiology
MH  - Enzyme Activation
MH  - GTP-Binding Proteins/physiology
MH  - HL-60 Cells
MH  - Humans
MH  - Luminescent Proteins/genetics
MH  - N-Formylmethionine Leucyl-Phenylalanine/pharmacology
MH  - Neutrophils/enzymology/physiology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Signal Transduction
MH  - Transfection
PMC - PMC2518103
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2008/08/30 09:00
MHDA- 2008/12/19 09:00
PMCR- 2008/08/27
CRDT- 2008/08/30 09:00
PHST- 2008/05/11 00:00 [received]
PHST- 2008/07/17 00:00 [accepted]
PHST- 2008/08/30 09:00 [pubmed]
PHST- 2008/12/19 09:00 [medline]
PHST- 2008/08/30 09:00 [entrez]
PHST- 2008/08/27 00:00 [pmc-release]
AID - 08-PONE-RA-04658R1 [pii]
AID - 10.1371/journal.pone.0003068 [doi]
PST - epublish
SO  - PLoS One. 2008 Aug 27;3(8):e3068. doi: 10.1371/journal.pone.0003068.