Abstract
Tumstatin is a 28-kilodalton fragment of type IV collagen that displays both anti-angiogenic and proapoptotic activity. Here we show that tumstatin functions as an endothelial cell-specific inhibitor of protein synthesis. Through a requisite interaction with alphaVbeta3 integrin, tumstatin inhibits activation of focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3-kinase), protein kinase B (PKB/Akt), and mammalian target of rapamycin (mTOR), and it prevents the dissociation of eukaryotic initiation factor 4E protein (eIF4E) from 4E-binding protein 1. These results establish a role for integrins in mediating cell-specific inhibition of cap-dependent protein synthesis and suggest a potential mechanism for tumstatin's selective effects on endothelial cells.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adaptor Proteins, Signal Transducing
-
Amino Acid Sequence
-
Animals
-
Autoantigens / chemistry
-
Autoantigens / metabolism
-
Autoantigens / pharmacology*
-
Carrier Proteins / metabolism
-
Cattle
-
Cell Cycle Proteins
-
Cells, Cultured
-
Collagen Type IV / chemistry
-
Collagen Type IV / metabolism
-
Collagen Type IV / pharmacology*
-
Endothelium, Vascular / cytology*
-
Endothelium, Vascular / drug effects
-
Endothelium, Vascular / metabolism*
-
Enzyme Activation / drug effects
-
Eukaryotic Initiation Factor-4E
-
Eukaryotic Initiation Factors
-
Focal Adhesion Kinase 1
-
Focal Adhesion Protein-Tyrosine Kinases
-
Humans
-
Mice
-
Molecular Sequence Data
-
Peptide Fragments / pharmacology
-
Peptide Initiation Factors / metabolism
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphoproteins / metabolism
-
Phosphorylation
-
Protein Biosynthesis* / drug effects
-
Protein Kinase Inhibitors
-
Protein Kinases / metabolism
-
Protein Serine-Threonine Kinases*
-
Protein Synthesis Inhibitors / pharmacology*
-
Protein-Tyrosine Kinases / metabolism
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins c-akt
-
RNA Caps / metabolism
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
Receptors, Vitronectin / metabolism
-
Signal Transduction
-
TOR Serine-Threonine Kinases
-
Tumor Cells, Cultured
Substances
-
Adaptor Proteins, Signal Transducing
-
Autoantigens
-
Carrier Proteins
-
Cell Cycle Proteins
-
Collagen Type IV
-
EIF4EBP1 protein, human
-
Eif4ebp1 protein, mouse
-
Eukaryotic Initiation Factor-4E
-
Eukaryotic Initiation Factors
-
Peptide Fragments
-
Peptide Initiation Factors
-
Phosphoproteins
-
Protein Kinase Inhibitors
-
Protein Synthesis Inhibitors
-
Proto-Oncogene Proteins
-
RNA Caps
-
RNA, Messenger
-
Receptors, Vitronectin
-
type IV collagen alpha3 chain
-
Protein Kinases
-
MTOR protein, human
-
mTOR protein, mouse
-
Protein-Tyrosine Kinases
-
Focal Adhesion Kinase 1
-
Focal Adhesion Protein-Tyrosine Kinases
-
PTK2 protein, human
-
Ptk2 protein, mouse
-
AKT1 protein, human
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt
-
TOR Serine-Threonine Kinases