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Metalloproteinases and the modulation of GH signaling

G Baumann1, S J Frank

  • 1Center for Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Medical School, 303 E Chicago Avenue, Chicago, IL 60611, USA.

The Journal of Endocrinology
|September 5, 2002
PubMed

Insights

Tumor necrosis factor-alpha-converting enzyme (TACE), or ADAM 17, cleaves the GH receptor (GHR), releasing GH-binding protein (GHBP). This process downregulates functional GHRs and impacts GH action.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Endocrinology

Background:

  • The growth hormone receptor (GHR) mediates growth hormone (GH) action.
  • Proteolytic cleavage of cell surface receptors is a mechanism for regulating their function.
  • Tumor necrosis factor-alpha-converting enzyme (TACE), also known as ADAM 17, is a metalloproteinase implicated in ectodomain shedding.

Purpose of the Study:

  • To investigate the role of TACE/ADAM 17 in GHR cleavage and GH-binding protein (GHBP) shedding.
  • To elucidate the signaling pathways involved in TACE-mediated GHR proteolysis.
  • To understand the consequences of GHR proteolysis on GH signaling.

Main Methods:

  • Cell-based assays using phorbol esters, platelet-derived growth factor, and serum to induce proteolysis.
  • Western blotting and ELISA to detect GHR cleavage and GHBP shedding.
  • Pharmacological inhibition of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) pathways.
  • Gamma-secretase inhibition to study GHR remnant processing.

Main Results:

  • TACE/ADAM 17 mediates the cleavage of GHR at the cell surface, releasing GHBP into the extracellular space.
  • GHR proteolysis is induced by phorbol esters, growth factors, and serum, and is dependent on PKC and partially on MAPK signaling.
  • The GHR remnant is further processed by gamma-secretase, potentially generating biologically active fragments.
  • GH binding to GHR induces dimerization, rendering the receptor resistant to TACE-mediated cleavage.
  • GHR proteolysis results in the downregulation of cell surface GHRs and affects GH signaling.

Conclusions:

  • TACE/ADAM 17 plays a critical role in GHR regulation through proteolysis.
  • GHR cleavage by TACE/ADAM 17 is a regulated process influenced by signaling pathways and GH itself.
  • The shedding of GHBP and processing of GHR remnants have significant implications for GH action and endocrine signaling.

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