PMID- 12909616
OWN - NLM
STAT- MEDLINE
DCOM- 20040105
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 43
DP  - 2003 Oct 24
TI  - RGD-containing peptides activate S6K1 through beta3 integrin in adult cardiac 
      muscle cells.
PG  - 42214-24
AB  - The enzyme p70S6 kinase (S6K1) is critical for cell growth, and we have reported 
      its activation during cardiac hypertrophy. Because cardiac hypertrophy also 
      involves integrin activation, we analyzed whether integrins could contribute to 
      S6K1 activation. Using adult feline cardiomyocytes, here we report that 
      integrin-interacting Arg-Gly-Asp (RGD) peptides activate S6K1 as observed by band 
      shifting, kinase activity and phosphorylation at Thr-389 and Thr-421/Ser-424 of 
      S6K1, and S6 protein phosphorylation. Perturbation of specific integrin function 
      with blocking antibodies and by overexpressing the beta1A cytoplasmic tail 
      revealed that beta3 but not beta1 integrin mediates the RGD-induced S6K1 
      activation. This activation is focal adhesion complex-independent and is 
      accompanied by the activation of extracellular signal-regulated kinases 1/2 (ERK) 
      and mammalian target of rapamycin (mTOR). Studies using specific inhibitors and 
      dominant negative c-Raf expression in cardiomyocytes indicate that the S6K1 
      activation involves mTOR, MEK/ERK, and phosphatidylinositol 3-kinase pathways and 
      is independent of protein kinase C and c-Raf. Finally, addition of 
      fluorescent-labeled RGD peptide to cardiomyocytes exhibits its internalization 
      and localization to the endocytic vesicles, and pretreatment of cardiomyocytes 
      with endocytic inhibitors reduced the S6K1 activation. These data suggest that 
      RGD interaction with beta3 integrin and its subsequent endocytosis trigger 
      specific signaling pathway(s) for S6K1 activation in cardiomyocytes and that this 
      process may contribute to hypertrophic growth and remodeling of myocardium.
FAU - Balasubramanian, Sundaravadivel
AU  - Balasubramanian S
AD  - Cardiology Division of the Department of Medicine, Gazes Cardiac Research 
      Institute, Medical University of South Carolina, 114 Doughty Street, Charleston, 
      SC 29425-2221, USA.
FAU - Kuppuswamy, Dhandapani
AU  - Kuppuswamy D
LA  - eng
GR  - HL 48788/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20030809
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Integrin beta3)
RN  - 0 (Oligopeptides)
RN  - 78VO7F77PN (arginyl-glycyl-aspartic acid)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
SB  - IM
MH  - Animals
MH  - Cardiomegaly/etiology
MH  - Cats
MH  - Cell Division
MH  - Cells, Cultured
MH  - Endocytosis
MH  - Focal Adhesions/physiology
MH  - Integrin beta3/*metabolism/physiology
MH  - Myocytes, Cardiac/*metabolism
MH  - Oligopeptides/*pharmacology
MH  - Phosphorylation
MH  - Ribosomal Protein S6 Kinases, 70-kDa/*metabolism
MH  - Signal Transduction
EDAT- 2003/08/12 05:00
MHDA- 2004/01/06 05:00
CRDT- 2003/08/12 05:00
PHST- 2003/08/12 05:00 [pubmed]
PHST- 2004/01/06 05:00 [medline]
PHST- 2003/08/12 05:00 [entrez]
AID - S0021-9258(20)82759-8 [pii]
AID - 10.1074/jbc.M303428200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Oct 24;278(43):42214-24. doi: 10.1074/jbc.M303428200. Epub 2003 
      Aug 9.