Abstract
B61 was originally described as a novel secreted tumor necrosis factor-alpha-inducible gene product in endothelial cells (Holzman, L. B., Marks, R. M., and Dixit, V. M. (1990) Mol. Cell. Biol. 10, 5830-5838). It was recently discovered that soluble recombinant B61 could serve as a ligand for the Eck receptor protein-tyrosine kinase, a member of the Eph/Eck subfamily of receptor protein-tyrosine kinases (Bartley, T.D., Hunt, R. W., Welcher, A. A., Boyle, W. J., Parker, V. P., Lindberg, R. A., Lu, H. S., Colombero, A. M., Elliott, R. L., Guthrie, R. A., Holst, P. L., Skrine, J. D., Toso, R. J., Zhang, M., Fernandez, E., Trail, G., Yarnum, B., Yarden, Y., Hunter, T., and Fox, G. M. (1994) Nature 368, 558-560). We now show that B61 can also exist as a cell surface glycosylphosphatidyl-inositol-linked protein that is capable of activating the Eck receptor protein-tyrosine kinase, the first such report of a receptor protein-tyrosine kinase ligand that is glycosylphosphatidylinositol-linked. In addition, the expression patterns of B61 and Eck during mouse ontogeny were determined by in situ hybridization. Both were found to be highly expressed in the developing lung and gut, while Eck was preferentially expressed in the thymus. Finally, the gene for B61 was localized to a specific position on mouse chromosome 3 by interspecific back-cross analysis.
Highlights
The first such ligand for a family member, Eck, was recently identified as the cytokineinducible immediate early response gene B61 that was originally cloned by differential hybridization from tumor necrosis factor-a-stimulated human umbilical vein endothelial cells (24)
The B61 gene product was shown to be a secreted 25-kDa protein found in the conditioned medium of tumor necrosis factor-a-treated endothelial cells (2)
Due to the presence of a characteristic stretch of hydrophobic residues at the C terminus that was reminiscent of the signal for glycosylphosphatidylinositol (GPl)l linkage, the possibility was raised that B61 may exist anchored to the cell surface as a GPI-linked protein (2)
Summary
Vol 270, No 10, Issue of March 10, pp. 5636-5641, 1995 Printed in U.S.A. Characterization of B61, the Ligand for the Eck Receptor Protein-Tyrosine Kinase*. To begin to understand the function of this family of receptor protein-tyrosine kinases, an important first step is the characterization of their cognate ligands The first such ligand for a family member, Eck, was recently identified as the cytokineinducible immediate early response gene B61 that was originally cloned by differential hybridization from tumor necrosis factor-a-stimulated human umbilical vein endothelial cells (24). Since the disruption of genes encoding receptor protein-tyrosine kinases or their respective ligands has been linked to a number of developmental anomalies (1), the chromosomal localization of B61 in the mouse genome was established. Cd1, Pklr, Gba, Fpsl-rs, OSI, Thbs Fegr, Cacy, 03Tu51, 861 Cd2 Alp1a1 Ampd-1, Tshb, Ngfb, Nras, Rapts 03Sel Amy-2 Amj>d·2
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