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Converting Enzyme (TACE) Is a Growth Hormone Binding Protein (GHBP) Sheddase: The Metalloprotease TACE/ADAM-17 Is Critical for (PMA-Induced) GH Receptor Proteolysis and GHBP Generation1
Department of Cell Biology (Y.Z., S.J.F.), University of Alabama at Birmingham, Birmingham, Alabama 35294; Department of Medicine (J.J., S.J.F.), Division of Endocrinology and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294; Immunex Corp. (R.A.B.), Seattle, Washington 98101; Center for Endocrinology (G.B.), Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611; and Veterans Affairs Medical Center (S.J.F.), Birmingham, Alabama 35294
Address all correspondence and requests for reprints to: Stuart J. Frank, University of Alabama at Birmingham, Room 756, DREB, 1808 7th Avenue South, Birmingham, Alabama 35294. E-mail: frank{at}endo.dom.uab.edu
The GH binding protein (GHBP), which exists in many vertebrates, is a
circulating high affinity binding protein corresponding to the
extracellular domain of the GH receptor (GHR). In humans, rabbits, and
several other species, the GHBP is generated by proteolysis of the GHR
and shedding of its extracellular domain. We previously showed that
GHBP shedding is inducible by the phorbol ester phorbol
12-myristate,13-acetate (PMA) and inhibited by the metalloprotease
inhibitor, Immunex Corp. Compound 3 (IC3). The metzincin
metalloprotease, tumor necrosis factor-
(TNF-)-converting enzyme
(TACE), catalyzes the shedding of TNF- from its transmembrane
precursor, a process that is also inhibitable by IC3. TACE may hence be
a candidate for GHBP sheddase. In this study, we reconstitute
fibroblasts derived from a TACE knockout mouse (Null cells) with either
the rabbit (rb) GHR alone (Null/R) or rbGHR plus murine TACE
(Null/R+T). Although GHR in both cells was expressed at similar
abundance, dimerized normally and caused JAK2 activation in response to
GH independent of TACE expression, PMA was unable to generate GHBP from
Null/R cells. In contrast, PMA caused ample GHBP generation from TACE
reconstituted (Null/R+T) cells, and this GHBP shedding was
substantially inhibited by IC3 pretreatment. Corresponding to the
induced shedding of GHBP from Null/R+T cells, PMA treatment caused a
significant loss of immunoblottable GHR in Null/R+T, but not in Null/R
cells. We conclude that TACE is an enzyme required for PMA-induced GHBP
shedding and that PMA-induced down-regulation of GHR abundance may in
significant measure be attributable to TACE-mediated GHR proteolysis.
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