PMID- 15708965
OWN - NLM
STAT- MEDLINE
DCOM- 20050707
LR  - 20211203
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 288
IP  - 6
DP  - 2005 Jun
TI  - Rapamycin inhibits fibronectin-induced migration of the human arterial smooth 
      muscle line (E47) through the mammalian target of rapamycin.
PG  - H2861-8
AB  - The matrix protein fibronectin (FN) is a potent agoinst of vascular smooth muscle 
      cell (SMC) migration. The role of rapamycin and the mammalian target of rapamycin 
      (mTOR) in matrix protein-induced migration has not yet been defined. In these 
      studies, we found that rapamycin (10 nM) markedly diminished chemotaxis of E47 
      cells (a cell line derived from human atherosclerotic plaques) and rat aortic 
      SMCs toward FN as well as type I collagen and laminin; however, a period of 
      preincubation >20 h was required. Subsequently, we showed that treatment with FN 
      induced a rapid activation of mTOR as well as its downstream effector, S6 kinase 
      (S6K). Moreover, FN-induced activation of both proteins was inhibited by 
      preincubation with rapamycin for only 30 min. We then explored the upstream 
      signaling pathway through which FN might mediate mTOR activation. A blocking 
      antibody to alpha(v)beta(3) inhibited FN-induced mTOR/S6K activation as well as 
      E47 cell chemotaxis, implicating alpha(v)beta(3) as the integrin receptor 
      responsible for initiating FN-induced migration. Moreover, preincubation of E47 
      cells with wortmannin or LY-294002 blocked FN-induced mTOR/S6K activation, 
      demonstrating that phosphatidylinositol 3-kinase (PI3K) plays a critical role in 
      this rapamycin-sensitive signaling pathway. It has been previously suggested that 
      rapamycin's effect on migration maybe related to enhancement of p27(kip1). 
      However, treatment of E47 cells with rapamycin did not alter the level of 
      p27(kip1) in the presence or absence of FN. Taken together, our data demonstrate 
      that rapamycin inhibits FN-induced SMC migration through a pathway that involves 
      at least alpha(v)beta(3)-integrin, PI3K, mTOR, and S6K.
FAU - Sakakibara, Kenji
AU  - Sakakibara K
AD  - Dept. of Surgery, New York Presbyterian Hospital, 525 E. 68th St., Payson 707, 
      New York, NY 10021, USA.
FAU - Liu, Bo
AU  - Liu B
FAU - Hollenbeck, Scott
AU  - Hollenbeck S
FAU - Kent, K Craig
AU  - Kent KC
LA  - eng
GR  - HL-68673/HL/NHLBI NIH HHS/United States
GR  - T32 GM-08466/GM/NIGMS 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 - 20050211
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Androstadienes)
RN  - 0 (Fibronectins)
RN  - 0 (Laminin)
RN  - 9007-34-5 (Collagen)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Arteries
MH  - Cell Line
MH  - Cell Movement/drug effects/*physiology
MH  - Chemotaxis/drug effects/*physiology
MH  - Collagen/pharmacology
MH  - Fibronectins/*antagonists & inhibitors/*pharmacology
MH  - Humans
MH  - Laminin/pharmacology
MH  - Muscle, Smooth, Vascular/drug effects/*physiology
MH  - Protein Kinases/*physiology
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Wortmannin
EDAT- 2005/02/15 09:00
MHDA- 2005/07/08 09:00
CRDT- 2005/02/15 09:00
PHST- 2005/02/15 09:00 [pubmed]
PHST- 2005/07/08 09:00 [medline]
PHST- 2005/02/15 09:00 [entrez]
AID - 00561.2004 [pii]
AID - 10.1152/ajpheart.00561.2004 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H2861-8. doi: 
      10.1152/ajpheart.00561.2004. Epub 2005 Feb 11.