PMID- 15964303
OWN - NLM
STAT- MEDLINE
DCOM- 20050823
LR  - 20211203
IS  - 0022-4804 (Print)
IS  - 0022-4804 (Linking)
VI  - 127
IP  - 1
DP  - 2005 Jul 1
TI  - Urokinase-induced smooth muscle cell migration requires PI3-K and Akt activation.
PG  - 46-52
AB  - OBJECTIVE: To examine the role of the phospho-inositol-3'-kinase (PI3-K)-akt 
      signaling axis during smooth muscle cell (SMC) migration in response to the 
      aminoterminal fragment of urokinase (ATF). BACKGROUND: Urokinase (uPA) is 
      involved in vessel remodeling and mediates smooth muscle cell migration. 
      Migration in response to urokinase is dependent on ATF. The role of PI3-K/akt 
      signaling during migration in response to the uPA fragments is not understood. 
      METHODS: Murine arterial SMCs were cultured in vitro. Linear wound and Boyden 
      microchemotaxis assays of migration were performed in the presence of ATF with 
      and without the PI3-K inhibitors (Wortmannin, Wn [10 nm] and LY294002, LY [10 
      microm]) and an akt inhibitor (aktI, [10 microm]). Western blotting was performed 
      for akt, ERK1/2, and GSK3beta phosphorylation after cells were stimulated with 
      ATF in the presence and absence of the inhibitors. Statistics were analyzed by 
      one-way ANOVA. RESULTS: Both PI3-K and akt inhibitors blocked the migratory 
      response to ATF in both assays. ATF induced time-dependent increases in akt 
      phosphorylation at both S472 and T308 sites and ERK1/2 phosphorylation. 
      Activation of akt and ERK1/2 was inhibited by Wn and LY. Manumycin A, a ras 
      inhibitor, did not inhibit activation of akt but did inhibit ERK1/2 activation. 
      Activation of akt and the dephosphorylation of its downstream kinase GSK3beta 
      were inhibited by the akt inhibitor. Direct inhibition of akt did not influence 
      ERK1/2 activation and inhibition of ERK1/2 did not influence akt activation. 
      CONCLUSION: ATF mediated migration is PI3-K dependent and activates two separate 
      pathways: ERK1/2 and akt. ATF induces akt phosphorylation through a PI3K-mediated 
      but ras-independent mechanism while both ras and PI3K are required for ERK1/2 
      activation. Defining key signaling pathways is vital to regulate vessel 
      remodeling.
FAU - Galaria, Irfan I
AU  - Galaria II
AD  - Division of Vascular Surgery, Department of Surgery, Center for Cardiovascular 
      Research, University of Rochester, Rochester, New York 14642, USA.
FAU - Nicholl, Suzanne M
AU  - Nicholl SM
FAU - Roztocil, Elisa
AU  - Roztocil E
FAU - Davies, Mark G
AU  - Davies MG
LA  - eng
GR  - K08 HL 67746/HL/NHLBI NIH HHS/United States
GR  - T32 HL 07949/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20050421
PL  - United States
TA  - J Surg Res
JT  - The Journal of surgical research
JID - 0376340
RN  - 0 (Androstadienes)
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Morpholines)
RN  - 0 (Peptide Fragments)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Aorta
MH  - Cell Movement/drug effects/*physiology
MH  - Cells, Cultured
MH  - Chemotaxis/drug effects/physiology
MH  - Chromones/pharmacology
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Mice
MH  - Morpholines/pharmacology
MH  - Muscle, Smooth, Vascular/drug effects/*physiology
MH  - Peptide Fragments/*pharmacology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Signal Transduction
MH  - Wortmannin
EDAT- 2005/06/21 09:00
MHDA- 2005/08/24 09:00
CRDT- 2005/06/21 09:00
PHST- 2004/12/21 00:00 [received]
PHST- 2005/02/22 00:00 [revised]
PHST- 2005/02/23 00:00 [accepted]
PHST- 2005/06/21 09:00 [pubmed]
PHST- 2005/08/24 09:00 [medline]
PHST- 2005/06/21 09:00 [entrez]
AID - S0022-4804(05)00098-3 [pii]
AID - 10.1016/j.jss.2005.02.022 [doi]
PST - ppublish
SO  - J Surg Res. 2005 Jul 1;127(1):46-52. doi: 10.1016/j.jss.2005.02.022. Epub 2005 
      Apr 21.