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J. Biol. Chem., Vol. 276, Issue 18, 15099-15106, May 4, 2001
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From the Columbia University College of Physicians and Surgeons,
Department of Medicine, New York, New York 10032
The interaction of hepatocyte growth factor (HGF)
with c-Met has been implicated in morphogenesis of the kidney,
lung, mammary gland, liver, placenta, and limb bud. HGF is secreted as
an inactive zymogen and must be cleaved by a serine protease to
initiate Met signaling. We show here that a serine protease specific
for HGF, HGF activator (HGFA), is expressed and activated by the
ureteric bud of the developing kidney in vivo and in
vitro. Inhibition of HGFA activity with serine protease
inhibitors reduced ureteric bud branching and inhibited
glomerulogenesis and nephrogenesis. Activated HGF rescued developing
kidneys from the effects of inhibitors. HGFA was localized around the
tips of the ureteric bud in developing kidneys, while HGF was expressed
diffusely throughout the mesenchyme. These data show that expression of
HGF is not sufficient for development, but that its activation is also
required. The localization of HGFA to the ureteric bud and the
mesenchyme immediately adjacent to it suggests that HGFA creates a
gradient of HGF activity in the developing kidney. The creation and
shape of gradients of activated HGF by the localized secretion of HGF
activators could play an important role in pattern formation by HGF
responsive tissues.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF224724.
Activation of Hepatocyte Growth Factor (HGF) by
Endogenous HGF Activator Is Required for Metanephric Kidney
Morphogenesis in Vitro*
,
*
This work was supported in part by March of Dimes Grant
1-FY98-0513. Confocal microscopy was performed at the Confocal
Microscopy Facility of Columbia University, which was established by
National Institutes of Health Shared Instrumentation Grant 1S10 RR10406 and is supported by National Institutes of Health Grant 5-P30-CA13696 as part of the Herbert Irving Cancer Center at Columbia University.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.
Established Investigator of the American Heart Association. To
whom correspondence should be addressed. Tel.: 212-305-4476; Fax:
212-305-3475; E-mail: jsv1@columbia.edu.
§
Partially supported by the Summer Undergraduate Research
Fund project of Columbia University.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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