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Science 4 January 2002:
Vol. 295. no. 5552, pp. 140 - 143
DOI: 10.1126/science.1065298
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Reports

Tumstatin, an Endothelial Cell-Specific Inhibitor of Protein Synthesis

Yohei Maeshima,1* Akulapalli Sudhakar,1* Julie C. Lively,2 Kohjiro Ueki,3 Surender Kharbanda,4dagger C. Ronald Kahn,3 Nahum Sonenberg,5 Richard O. Hynes,2 Raghu Kalluri1ddagger

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 alpha Vbeta 3 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.

1 Program in Matrix Biology, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
2 Department of Biology, Howard Hughes Medical Institute, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3 Joslin Diabetes Center and Harvard Medical School,
4 Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
5 Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada H3G 1V6.
*   These authors contributed equally to this work.

dagger    Present address: Ilex Oncology, Boston, MA 02216, USA.

ddagger    To whom correspondence should be addressed. E-mail: rkalluri{at}caregroup.harvard.edu

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