Metalloprotease-mediated GH Receptor Proteolysis and GHBP Shedding

Wang, Xiangdong; He, Kai; Gerhart, Mary; Huang, Yao; Jiang, Jing; Paxton, Raymond J.; Yang, Shaohua; Lü, Chunxia; Menon, Ram K.; Black, Roy A.; Baumann, Gerhard; Frank, Stuart J.

doi:10.1074/jbc.m208738200

Cited by 77 publications

(32 citation statements)

References 42 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3A). Their size was consistent with the precursor and mature forms of the receptor, as shown previously in GHR-expressing cells and tissues of other species (Yi et al 1996, Beauloye et al 2002, Wang et al 2002. Of these two bands, only the upper band was tyrosine-phosphorylated in response to GH (Fig 3A), confirming its identity with the mature form of the bovine GHR (Yi et al 1996, Beauloye et al 2002, Wang et al 2002.…”

Section: Onset Of Lactation Is Associated With Decreased Hepatic Ghr supporting

confidence: 65%

Dairy cows experience selective reduction of the hepatic growth hormone receptor during the periparturient period

Kim¹,

Rhoads²,

Block³

et al. 2004

Journal of Endocrinology

View full text Add to dashboard Cite

At parturition, dairy cows experience a 70% reduction in plasma IGF-I. This reduction coincides with decreased abundance of GHR1A, the liver-specific transcript of the growth hormone receptor (GHR) gene, suggesting impaired growth hormone-dependent synthesis of IGF-I. It is not immediately obvious that the periparturient reduction in GHR1A is sufficient to reduce hepatic GHR abundance. This is because 50% of total GHR mRNA abundance in prepartum liver is accounted for by ubiquitously expressed transcripts which remain collectively unchanged at parturition. In addition, the possibility that parturition alters GHR expression in other growth hormone target tissue has not been examined. To address these questions, we measured GHR gene expression and GHR protein in liver and skeletal muscle of four dairy cows on days -35,+3 and+56 (relative to parturition on day 0). Hepatic GHR abundance and GHR1A transcripts were lower on day+3 than on day -35 and returned to late pregnancy value by day+56. Additional studies in two other groups of cows indicated that the hepatic levels of the GHR protein recovered substantially within 10 days after parturition. These changes occurred without variation in the abundance of HNF4, a liver-enriched transcription factor activating the promoter responsible for GHR1A synthesis. In contrast to liver, levels of GHR gene expression and GHR protein were identical on days -35,+3 and+56 in skeletal muscle. These data suggest a role for the GHR in regulating tissue-specific changes in growth hormone responsiveness in periparturient dairy cows.

show abstract

Section: Onset Of Lactation Is Associated With Decreased Hepatic Ghr supporting

confidence: 65%

Dairy cows experience selective reduction of the hepatic growth hormone receptor during the periparturient period

Kim¹,

Rhoads²,

Block³

et al. 2004

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…Concentrated media samples (20 g) were assayed for their ability to cleave an ACE2-specific fluorogenic substrate as described under "Materials and Methods." clude that this is due to the divergence of sequence in the juxtamembrane region, it is important to note that ADAM17 appears to be able to cleave a diverse array of sequences (21)(22)(23). Indeed, it has been suggested that the structure of the stalk region may be a more important determinant of susceptibility to secretase cleavage than the amino acid sequence around the cleavage site (35,36).…”

Section: Discussionmentioning

confidence: 99%

“…20). The best characterized ADAM protease to date is ADAM17, or TNF-␣-converting enzyme, which was first identified as the sheddase for TNF-␣ but has subsequently been implicated in the shedding of other cell surface proteins (21)(22)(23). Other members of the ADAM family of proteinases, particularly ADAM9, ADAM10, and ADAM12, have been implicated as candidate sheddases for a wide range of proteins including APP, CXCL16, and heparin-binding epidermal growth factor (24 -27).…”

mentioning

confidence: 99%

Tumor Necrosis Factor-α Convertase (ADAM17) Mediates Regulated Ectodomain Shedding of the Severe-acute Respiratory Syndrome-Coronavirus (SARS-CoV) Receptor, Angiotensin-converting Enzyme-2 (ACE2)

Lambert

Yarski

Warner

et al. 2005

Journal of Biological Chemistry

655

717

View full text Add to dashboard Cite

Angiotensin-converting enzyme-2 (ACE2) is a critical regulator of heart function and a cellular receptor for the causative agent of severe-acute respiratory syndrome (SARS), SARS-CoV (coronavirus). ACE2 is a type I transmembrane protein, with an extracellular N-terminal domain containing the active site and a short intracellular C-terminal tail. A soluble form of ACE2, lacking its cytosolic and transmembrane domains, has been shown to block binding of the SARS-CoV spike protein to its receptor. In this study, we examined the ability of ACE2 to undergo proteolytic shedding and investigated the mechanisms responsible for this shedding event. We demonstrated that ACE2, heterologously expressed in HEK293 cells and endogenously expressed in Huh7 cells, undergoes metalloproteinase-mediated, phorbol ester-inducible ectodomain shedding. By using inhibitors with differing potency toward different members of the ADAM (a disintegrin and metalloproteinase) family of proteases, we identified ADAM17 as a candidate mediator of stimulated ACE2 shedding. Furthermore, ablation of ADAM17 expression using specific small interfering RNA duplexes reduced regulated ACE2 shedding, whereas overexpression of ADAM17 significantly increased shedding. Taken together, these data provided direct evidence for the involvement of ADAM17 in the regulated ectodomain shedding of ACE2. The identification of ADAM17 as the protease responsible for ACE2 shedding may provide new insight into the physiological roles of ACE2.

show abstract

“…Figure 3 summarizes the GHR cleavage events as presently understood. TACE, activated through PKC-and MAPK-dependent mechanisms, cleaves the (monomeric) GHR in the stem region at a presently unknown site (preliminary experiments have identified a murine GHR cleavage site nine residues amino-terminal to the first intramembranous amino acid (Wang et al 2002)). This generates the soluble GHBP and a GHR remnant consisting of the transmembrane and intracellular domains.…”

Section: Regulation Of Ghbp Sheddingmentioning

confidence: 99%

Metalloproteinases and the modulation of GH signaling

Baumann¹,

Frank²

2002

Journal of Endocrinology

View full text Add to dashboard Cite

The metzincin metalloproteinase, tumor necrosis factor--converting enzyme (TACE), also known as ADAM (a disintegrin and metalloproteinase) 17, has recently been identified as an important enzyme for cleavage of the GH receptor (GHR) and shedding of GH-binding protein (GHBP). Proteolysis can be induced by phorbol esters, platelet-derived growth factor and serum; it is dependent on protein kinase C and partially on MAP kinase pathways. Proteolysis occurs at the cell surface, leading to extracellular release of GHBP and intracellular GHR remnant accumulation. The GHR remnant is further processed by -secretase activity, possibly leading to biologically active products. TACE-dependent GHR proteolysis can be inhibited by GH as the dimerized GHR is resistant to cleavage. The cleavage site lies within a short juxtamembranous stem region that extends between the transmembrane helix and the globular dimerization domain of the GHR. GHR proteolysis leads to downregulation of functional GHRs at the cell surface, and has complex secondary effects on GH action via GHBP and GHR remnant generation.

show abstract

Metalloprotease-mediated GH Receptor Proteolysis and GHBP Shedding

Cited by 77 publications

References 42 publications

Dairy cows experience selective reduction of the hepatic growth hormone receptor during the periparturient period

Dairy cows experience selective reduction of the hepatic growth hormone receptor during the periparturient period

Tumor Necrosis Factor-α Convertase (ADAM17) Mediates Regulated Ectodomain Shedding of the Severe-acute Respiratory Syndrome-Coronavirus (SARS-CoV) Receptor, Angiotensin-converting Enzyme-2 (ACE2)

Metalloproteinases and the modulation of GH signaling

Contact Info

Product

Resources

About