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J. Biol. Chem., Vol. 277, Issue 39, 35990-35998, September 27, 2002
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From the Lombardi Cancer Center, Georgetown University, Washington,
D. C. 2007
Midkine (MK) is a developmentally regulated,
secreted growth factor homologous to pleiotrophin (PTN). To investigate
the potential role of MK in tumor growth, we expressed MK in human
SW-13 cells and studied receptor binding, signal transduction, and
activity of MK. The MK protein stimulates soft agar colony formation
in vitro and tumor growth of SW-13 cells in athymic nude
mice, as well as proliferation of human endothelial cells from brain
microvasculature and umbilical vein (HUVEC) in the low ng/ml range. MK
binds to anaplastic lymphoma kinase (ALK), the receptor for PTN, with
an apparent Kd of 170 pM in intact
cells, and this receptor binding of MK is competed by PTN with an
apparent Kd of ~20 pM. Monoclonal
antibodies raised against the extracellular ligand-binding domain of
ALK inhibit ALK receptor binding of MK as well as MK-stimulated colony
formation of SW-13 cells. Furthermore, MK stimulates ALK
phosphorylation in WI-38 human fibroblasts and activates PI3-kinase and
MAP kinase signal transduction in WI-38, HUVEC, neuroblastoma (SH
SY-5Y) and glioblastoma (U87MG) cells that express the ALK protein.
We conclude that MK can act as a growth, survival, and
angiogenic factor during tumorigenesis and signals through the ALK receptor.
Midkine Binds to Anaplastic Lymphoma Kinase (ALK) and Acts as
a Growth Factor for Different Cell Types*
*
This work was supported in part by grants from the National
Institutes of Health/National Cancer Institute (SPORE CA58185 to
A. W.) and by a fellowship from the National Institute on Drug Abuse
(to E. B. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Lombardi Cancer
Center, Georgetown University, 3970 Reservoir Rd., N. W., Washington, D. C. 20007. Tel.: 202-687-3672; Fax: 202-687-4821; E-mail:
wellstea@georgetown.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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