Metalloproteinases and the modulation of GH signaling

Baumann, Gerhard; Frank, S.J.

doi:10.1677/joe.0.1740361

Cited by 40 publications

(21 citation statements)

References 20 publications

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“…The most consistent cleavage site feature among ADAM substrates is that they usually reside in a stalk region between the membrane and an initial globular extracellular subdomain (35). Our findings for the rbGHR cleavage site fit well in this regard with the GHR being an ADAM substrate (34,44). Indeed, the crystal structure suggests that a short stem of roughly ten residues lies between the transmembrane domain and the beginning of extracellular subdomain 2, which contains the receptor dimerization domain (33).…”

supporting

confidence: 80%

“…Proteolytic Susceptibility of rbGHR Cleavage Region Mutants-There is no clear consensus sequence for cleavage among the various TACE substrates (34). While the determinants for proteolysis are not known in all cases, the distance of the site of cleavage from the membrane or the position of the cleavage site relative to globular extracellular domain regions have been suggested as important determinants (35).…”

Section: Adenovirally Expressed C-terminal Epitope-tagged Rbghr Cytopmentioning

confidence: 99%

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Metalloprotease-mediated GH Receptor Proteolysis and GHBP Shedding

Wang¹,

He²,

Gerhart³

et al. 2002

Journal of Biological Chemistry

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Growth hormone-binding protein (GHBP) is complexed to a substantial fraction of circulating GH. In humans, rabbits, and other species, GHBP derives from proteolytic shedding of the GH receptor (GHR) extracellular domain. In cell culture studies, stimuli such as phorbol ester, platelet-derived growth factor, or serum induce GHR proteolysis, which concomitantly yields shed GHBP in cell supernatants and a cell-associated cytoplasmic domain-containing GHR remnant. This process is sensitive to metalloprotease inhibition, and genetic reconstitution studies identify tumor necrosis factor-␣ converting enzyme (TACE/ADAM-17), a transmembrane metalloprotease, as a GHR sheddase. Stimuli that induce GHR proteolysis render cells less responsive to GH, but the mechanism(s) of this desensitization is not yet understood. In this study, we mapped the rabbit (rb) GHR cleavage site. We adenovirally expressed a C-terminal epitope-tagged rbGHR lacking most of its cytoplasmic domain, purified the remnant protein induced by the phorbol ester, PMA, and derived the cleavage site by N-terminal sequencing of the purified remnant. The N-terminal sequence, 239 FTCEEDFR 246 , matched perfectly the rbGHR and suggests that cleavage occurs eight residues from the membrane in the proximal extracellular domain stem region. Deletion and alanine substitution mutagenesis indicated that, similar to other TACE substrates, the spacing of residues in this region, more than their identity, influences GHR cleavage susceptibility. Further, we determined that PMA pretreatment desensitized a cleavage-sensitive GHR mutant, but not a cleavage-insensitive mutant, to GH-induced JAK2 activation. These results suggest that inducible GHR proteolysis can regulate GH signaling.

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supporting

confidence: 80%

Section: Adenovirally Expressed C-terminal Epitope-tagged Rbghr Cytopmentioning

confidence: 99%

Metalloprotease-mediated GH Receptor Proteolysis and GHBP Shedding

Wang¹,

He²,

Gerhart³

et al. 2002

Journal of Biological Chemistry

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“…Recent NMR structural studies of IFNaR2 indicate that the region containing the cleavage site predicted by our data lies immediately distal to a well-defined fibronectin-like domain of the IFNaR2 ectodomain, within a short, stalk-like juxtamembrane region (Chill et al, 2003). Similarly, the TACE cleavage site in the growth hormone receptor also resides in a structurally similar JM region (Baumann and Frank, 2002). It appears that both stalk length and sequence are critical determinants of TACE cleavage (Hinkle et al, 2004).…”

Section: Discussionsupporting

confidence: 57%

Regulated proteolysis of the IFNaR2 subunit of the interferon-alpha receptor

et al. 2004

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The type I interferons (IFNs) bind surface receptors, induce JAK kinases and activate STAT transcription factors to stimulate the transcription of genes downstream of IFN-stimulated response elements (ISREs). In this study, we demonstrate that IFNaR2, a subunit of the type I IFN receptor, is proteolytically cleaved in a regulated manner. Immunoblotting shows that multi-step cleavage occurs in response to phorbol ester (PMA) and IFN-a, generating both a transmembrane 'stub' and the intracellular domain (ICD), similar to Notch proteolysis. Isolated membrane fractions process IFNaR2 to release the ICD. A chimeric receptor construct is utilized to show that cleavage requires the presenilins and occurs in response to epidermal growth factor and protein kinase C-d overexpression, as well as PMA and type I IFNs. Fluorescence microscopy demonstrates that a green fluorescent protein-ICD fusion localizes predominantly to the nucleus. A fusion between the ICD and the Gal4 DNA-binding domain represses transcription, in a histone deacetylasedependent manner, of a Gal4 upstream activating sequence-regulated reporter, while overexpression of the ICD alone represses transcription of a reporter linked to an ISRE. Proteolytic cleavage events may facilitate receptor turnover or, more likely, function as a mechanism for signaling similar to that employed by Notch and the Alzheimer's precursor protein.

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“…In humans, the extracellular ligand binding domain of the growth hormone receptor is released from the cell surface via proteolysis, which decreases the responsiveness of target cells. Additionally, the presence of the released growth hormone receptor ectodomain in serum leads to a decrease in the concentration of free growth hormone (33). Analogous ectodomain shedding is observed with other single-span transmembrane receptors, including the tumor necrosis factor and the interleukin-6 receptors.…”

Section: Discussionmentioning

confidence: 85%

Proteolytic Shedding of the Extracellular Domain of Photoreceptor Cadherin

Rattner¹,

Chen²,

Nathans

2004

Journal of Biological Chemistry

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Photoreceptor cadherin (prCAD) is a distinctive cadherin family member that is concentrated at the base of rod and cone outer segments and is required for their structural integrity. During retinal development, prCAD localizes to the site of the future outer segment before rhodopsin or other phototransduction proteins. In vivo, prCAD undergoes a single proteolytic cleavage that releases the ectodomain as a soluble fragment. The C-terminal fragment containing the transmembrane and cytosolic domains remains associated with the outer segment. In rds(؊/؊) retinas, in which outer segment assembly is severely disrupted because of the absence of retinal degeneration slow (RDS)/peripherin, an essential outer segment structural protein, the level of prCAD is increased, whereas the levels of other outer segment proteins are decreased relative to wild type retinas. Additionally, the ratio of intact:cleaved prCAD polypeptides is increased in rds(؊/؊) retinas. These data imply that prCAD ectodomain cleavage is an integral part of the outer segment assembly process, and they further suggest that outer segment assembly might be driven, at least in part, by the near irreversibility of proteolysis.In the vertebrate retina, phototransduction occurs within the outer segments (OSs) 1 of rod and cone photoreceptors. The OS is a modified cilium that projects from the apical face of the photoreceptor cell toward the overlying retinal pigment epithelium (RPE). In mammals, the typical rod OS is ϳ1 m in diameter and ϳ30 -50 m in length. Each rod OS consists of a stack of ϳ1,000 flattened membrane sacs, referred to as discs, surrounded by plasma membrane. The light-absorbing visual pigments reside within the disc and plasma membranes at millimolar concentrations; other less abundant phototransduction proteins reside within one or both of these membranes or within the cytosolic space between adjacent discs.The OS of both rods and cones are subject to constant renewal throughout the life of the organism, with synthesis and assembly of new discs at the base of the OS and with RPEmediated phagocytosis and degradation of the oldest discs at the tip of the OS (1). In mammals, each disc requires ϳ10 days to move along the length of the OS, implying that each photoreceptor assembles ϳ100 new OS discs/day. All of the OS protein and lipid constituents originate in the cell body proper and are funneled through the thin connecting cilium to the site of assembly in the OS. The most widely accepted model for OS disc assembly, based on electron microscopic analyses of primate photoreceptors, posits that nascent discs form by evagination at the base of the OS and that as they enlarge and move distally they become progressively enclosed in plasma membrane (2).The precisely orchestrated synthesis, transport, and assembly of proteins and lipids into an almost crystalline array of OS discs raise numerous questions regarding underlying mechanisms. What controls the regular evagination of plasma membrane to form new discs? What determines the size and shape of...

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Metalloproteinases and the modulation of GH signaling

Cited by 40 publications

References 20 publications

Metalloprotease-mediated GH Receptor Proteolysis and GHBP Shedding

Metalloprotease-mediated GH Receptor Proteolysis and GHBP Shedding

Regulated proteolysis of the IFNaR2 subunit of the interferon-alpha receptor

Proteolytic Shedding of the Extracellular Domain of Photoreceptor Cadherin

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