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TIMP3 Modulates GHR Abundance and GH Sensitivity

Published on Jun 1, 2016in Molecular Endocrinology3.628
· DOI :10.1210/me.2015-1302
Yue Zhang15
Estimated H-index: 15
(UAB: University of Alabama at Birmingham),
Xiangdong Wang16
Estimated H-index: 16
(SDU: Shandong University)
+ 4 AuthorsStuart J. Frank45
Estimated H-index: 45
(UAB: University of Alabama at Birmingham)
Abstract
GH receptor (GHR) binds GH at the cell surface via its extracellular domain and initiates intracellular signal transduction, resulting in important anabolic and metabolic actions. GH signaling is subject to dynamic regulation, which in part is exerted by modulation of cell surface GHR levels. Constitutive and inducible metalloprotease-mediated cleavage of GHR regulate GHR abundance and thereby modulate GH action. We previously demonstrated that GHR proteolysis is catalyzed by the TNF-α converting enzyme (TACE; ADAM17). Tissue inhibitors of metalloproteases-3 (TIMP3) is a natural specific inhibitor of TACE, although mechanisms underlying this inhibition are not yet fully understood. In the current study, we use two model cell lines to examine the relationships between cellular TACE, TIMP3 expression, GHR metalloproteolysis, and GH sensitivity. These two cell lines exhibited markedly different sensitivity to inducible GHR proteolysis, which correlated directly to their relative levels of mature TACE vs unpr...
  • References (78)
  • Citations (4)
References78
Newest
The metalloproteinase ADAM17 (a disintegrin and metalloprotease 17) controls EGF receptor (EGFR) signaling by liberating EGFR ligands from their membrane anchor. Consequently, a patient lacking ADAM17 has skin and intestinal barrier defects that are likely caused by lack of EGFR signaling, and Adam17−/− mice die perinatally with open eyes, like Egfr−/− mice. A hallmark feature of ADAM17-dependent EGFR ligand shedding is that it can be rapidly and posttranslationally activated in a manner that re...
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#1Rong Ma (LSU Health Sciences Center New Orleans)H-Index: 2
#2Baihan Gu (LSU Health Sciences Center New Orleans)H-Index: 3
Last. Yuping Wang (LSU Health Sciences Center New Orleans)H-Index: 1
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Problem To determine whether down-regulation of TIMP3 expression promotes TACE expression and increases in TNFα production by placental trophoblast cells. Method of study Placental expression of TIMP3 and TACE was examined by immunostaining and Western blot. Effects of TIMP3 on TACE expression and TNFα production were assessed by transfection of TIMP3 siRNA into trophoblasts isolated from normal placentas. Effects of oxidative stress on trophoblast TIMP3 expression and TNFα production were also ...
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Protein ectodomain shedding by ADAM17 (a disintegrin and metalloprotease 17), a principal regulator of EGF-receptor signaling and TNFα release, is rapidly and posttranslationally activated by a variety of signaling pathways, and yet little is known about the underlying mechanism. Here, we report that inactive rhomboid protein 2 (iRhom2), recently identified as essential for the maturation of ADAM17 in hematopoietic cells, is crucial for the rapid activation of the shedding of some, but not all s...
88 CitationsSource
#1Linn E. Moore (U of A: University of Alberta)H-Index: 5
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Remodeling of the myocardium and the extracellular matrix (ECM) occurs in heart failure irrespective of its initial cause. The ECM serves as a scaffold to provide structural support as well as housing a number of cytokines and growth factors. Hence, disruption of the ECM will result in structural instability as well as activation of a number of signaling pathways that could lead to fibrosis, hypertrophy, and apoptosis. The ECM is a dynamic entity that undergoes constant turnover, and the integri...
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#2Jianming Liu (UCSF: University of California, San Francisco)H-Index: 5
Last. Rik Derynck (UCSF: University of California, San Francisco)H-Index: 114
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Ectodomain shedding mediated by tumor necrosis factor–α (TNF-α)–converting enzyme [TACE; also known as ADAM17 (a disintegrin and metalloproteinase 17)] provides an important switch in regulating cell proliferation, inflammation, and cancer progression. TACE-mediated ectodomain cleavage is activated by signaling of the mitogen-activated protein kinases (MAPKs) p38 and ERK (extracellular signal–regulated kinase). Here, we found that under basal conditions, TACE was predominantly present as dimers ...
93 CitationsSource
#1David R. McIlwain (U of T: University of Toronto)H-Index: 13
#2Philipp A. Lang (HHU: University of Düsseldorf)H-Index: 54
Last. Tak W. Mak (U of T: University of Toronto)H-Index: 139
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Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. A key mediator of septic shock is tumor necrosis factor–α (TNFα), which is shed from the plasma membrane after cleavage by the TNFα convertase (TACE). We report that the rhomboid family member iRhom2 interacted with TACE and regulated TNFα shedding. iRhom2 was critical for TACE maturation and trafficking to the cell surface in hematopoietic cells. Gene-targeted iRhom2-deficient mice showed reduc...
194 CitationsSource
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The cytokine tumor necrosis factor (TNF) is the primary trigger of inflammation. Like many extracellular signaling proteins, TNF is synthesized as a transmembrane protein; the active signal is its ectodomain, which is shed from cells after cleavage by an ADAM family metalloprotease, ADAM17 (TNFα-converting enzyme, TACE). We report that iRhom2 (RHBDF2), a proteolytically inactive member of the rhomboid family, is required for TNF release in mice. iRhom2 binds TACE and promotes its exit from the e...
228 CitationsSource
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#2Yu Wan (WHU: Wuhan University)H-Index: 12
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GH receptor (GHR) mediates the anabolic and metabolic effects of GH. We previously characterized a monoclonal antibody (anti-GHRext-mAb) that reacts with subdomain 2 of the rabbit GHR extracellular domain (ECD) and is a conformation-specific inhibitor of GH signaling in cells bearing rabbit or human GHR. Notably, this antibody has little effect on GH binding and also inhibits inducible metalloproteolysis of the GHR that occurs in the perimembranous ECD stem region. In the current study, we demon...
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