Unaltered Cleavage and Secretion of Angiotensin-converting Enzyme in Tumor Necrosis Factor-α-converting Enzyme-deficient Mice

Sadhukhan, Ramkrishna; Santhamma, Kizhakkekara R.; Reddy, P. Madhusudhana; Peschon, Jacques J.; Black, Roy A.; Sen, Indira

doi:10.1074/jbc.274.15.10511

Cited by 51 publications

(51 citation statements)

References 24 publications

(33 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Neither differed from wild-type testis ACE in terms of rapid release rates. This question is of considerable interest, in light of increasing evidence that the ACE secretase differs from the TNF-α convertase [16,17] and this may also extend to its recognition and activation characteristics.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Shedding of somatic angiotensin-converting enzyme (ACE) is inefficient compared with testis ACE despite cleavage at identical stalk sites

Woodman

Oppong

Cook

et al. 2000

Biochemical Journal

View full text Add to dashboard Cite

The somatic and testis isoforms of angiotensin-converting enzyme (ACE) are both C-terminally anchored ectoproteins that are shed by an unidentified secretase. Although testis and somatic ACE both share the same stalk and membrane domains the latter was reported to be shed inefficiently compared with testis ACE, and this was ascribed to cleavage at an alternative site [Beldent, Michaud, Bonnefoy, Chauvet and Corvol (1995) J. Biol. Chem. 270, 28962-28969]. These differences constitute a useful model system of the regulation and substrate preferences of the ACE secretase, and hence we investigated this further. In transfected Chinese hamster ovary cells, human somatic ACE (hsACE) was indeed shed less efficiently than human testis ACE, and shedding of somatic ACE responded poorly to phorbol ester activation. However, using several analytical techniques, we found no evidence that the somatic ACE cleavage site differed from that characterized in testis ACE. First, anti-peptide antibodies raised to specific sequences on either side of the reported cleavage site (Arg""$(\Leu""$)) clearly recognized soluble porcine somatic

show abstract

Section: Discussionmentioning

confidence: 99%

“…Tumour necrosis factor-α (TNF-α) convertase, a disintegrin Zn-metalloprotease, was the first sheddase to be isolated and characterized [13,14]. The ACE secretase appears to be similar to, but is distinct from, TNF-α convertase [15][16][17]. Although readily detected in i o, the functions of soluble ACE are unknown.…”

Section: Introductionmentioning

confidence: 99%

Shedding of somatic angiotensin-converting enzyme (ACE) is inefficient compared with testis ACE despite cleavage at identical stalk sites

Woodman

Oppong

Cook

et al. 2000

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…In most of these instances, TACE is required for the increased shedding seen in response to stimulation by phorbol ester, although the TACE-mediated release of erbB-4 is also enhanced by pervanadate, a tyrosine phosphatase inhibitor (35). Additional proteases must be involved in stimulated shedding, as TACE is not responsible for the release of ACE (39), TRANCE (40), or syndecan-1 and -4 (41). Furthermore, for most ectodomain shedding events it remains an open question whether one or several proteases are involved.…”

mentioning

confidence: 99%

Evidence for a Critical Role of the Tumor Necrosis Factor α Convertase (TACE) in Ectodomain Shedding of the p75 Neurotrophin Receptor (p75NTR)

Weskamp

Schlöndorff

Lum

et al. 2004

Journal of Biological Chemistry

138

114

View full text Add to dashboard Cite

Protein ectodomain shedding, the proteolytic release of the extracellullar domain of membrane-tethered proteins, can dramatically affect the function of cell surface receptors, growth factors, cytokines, and other proteins. In this study, we evaluated the activities involved in ectodomain shedding of p75 NTR , a neurotrophin receptor with critical roles in neuronal differentiation and survival. p75 NTR is shed in a variety of cell types, including dorsal root ganglia cells and PC12 cells. In Chinese hamster ovary cells, inhibitors of the MEK/ERK and p38 MAP kinase pathways uncovered distinct signaling pathways required for the constitutive and stimulated shedding of p75 NTR . Stimulated p75 NTR shedding is abrogated in M2 mutant Chinese hamster ovary cells that lack functional tumor necrosis factor-␣ converting enzyme (TACE, also referred to as ADAM17) and in cells isolated from adam17؊/؊ mice, but not in cells from adam9/12/15؊/؊ or adam10؊/؊ mice. Stimulated p75 NTR shedding is strongly reduced by deletion of 15 amino acid residues in its extracellular membrane-proximal stalk domain. However, similar to other shed proteins, point mutations and overlapping shorter deletions within this region have little or no effect on shedding. Because ectodomain shedding of p75 NTR releases a soluble ectodomain and could also be a prerequisite for its regulated intramembrane proteolysis, these findings may have important implications for the functional regulation of p75 NTR .Protein ectodomain shedding is emerging as an important post-translational mechanism for regulating the function of membrane-anchored proteins. Shedding involves the proteolytic processing of membrane-tethered proteins leading to the release of their extracellular-or ectodomain (reviewed in Refs. 1-4). About 2-4% of the proteins on the cell surface are released by metalloproteases in response to phorbol ester stimulation (5). These molecules comprise a variety of structurally and functionally distinct proteins, including epidermal growth factor receptor ligands such as TGF␣ 1 and HB-EGF, TNF family members, and other cytokines, receptors such as the p55 and p75 TNF receptors and the interleukin-6 receptor, and several other proteins, including the amyloid precursor protein, Notch, and Delta (see Ref. 3 and references therein). Ectodomain shedding has been shown to be essential for proper signaling via epidermal growth factor receptor ligands (6 -15), Notch-mediated lateral inhibition (16 -23), limiting TNFR-mediated inflammatory reactions (24), and regulating axonal guidance (25)(26)(27). Even if the functional consequences of ectodomain release remain to be evaluated for most shed proteins, it seems likely that ectodomain shedding will affect the function of the majority of its substrate proteins.Despite the growing number of proteins that are known to undergo ectodomain shedding, much remains to be learned about the mechanisms underlying this process and the responsible proteases. The TNF␣ convertase (TACE) is one of the first proteases shown to be in...

show abstract

“…Physiologically relevant molecules whose ectodomains are shed include membrane-anchored growth factors [1], some of their receptors [4][5][6][7][8][9], cell adhesion proteins [10], ectoenzymes [11], molecules involved in immune responses [2] and proteins, such as the β-amyloid precursor protein ( βAPP), whose function has not been fully elucidated [2]. Alterations in the cleavage of some of these membrane proteins may lead to disease.…”

Section: Introductionmentioning

confidence: 99%

“…It is possible that other proteases may be involved in the regulation of membrane-protein ectodomain cleavage. In fact, solubilization of the ectodomain of the angiotensin converting enzyme is unaffected in fibroblasts derived from TACE-deficient animals [11], and studies on the solubilization of pro-heparin binding epidermal growth factor (EGF)-like growth factor (proHB-EGF) have indicated that other ADAM family members, such as MDC9\ADAM9\Meltrin-γ, may also participate in the release of soluble forms of membrane-bound molecules [22]. A characteristic of the activity of membrane secretases is their highly regulated nature.…”

Section: Introductionmentioning

confidence: 99%

Stimulation of cleavage of membrane proteins by calmodulin inhibitors

et al. 2000

View full text Add to dashboard Cite

The ectodomain of several membrane-bound proteins can be shed by proteolytic cleavage. The activity of the proteases involved in shedding is highly regulated by several intracellular second messenger pathways, such as protein kinase C (PKC) and intracellular Ca# + . Recently, the shedding of the adhesion molecule L-selectin has been shown to be regulated by the interaction of calmodulin (CaM) with the cytosolic tail of L-selectin. Prevention of CaM-L-selectin interaction by CaM inhibitors or mutation of a CaM binding site in L-selectin induced L-selectin ectodomain shedding. Whether this action of CaM inhibitors also affects other membrane-bound proteins is not known. In the present paper we show that CaM inhibitors also stimulate the cleavage of several other transmembrane proteins, such

show abstract

Unaltered Cleavage and Secretion of Angiotensin-converting Enzyme in Tumor Necrosis Factor-α-converting Enzyme-deficient Mice

Cited by 51 publications

References 24 publications

Shedding of somatic angiotensin-converting enzyme (ACE) is inefficient compared with testis ACE despite cleavage at identical stalk sites

Shedding of somatic angiotensin-converting enzyme (ACE) is inefficient compared with testis ACE despite cleavage at identical stalk sites

Evidence for a Critical Role of the Tumor Necrosis Factor α Convertase (TACE) in Ectodomain Shedding of the p75 Neurotrophin Receptor (p75NTR)

Stimulation of cleavage of membrane proteins by calmodulin inhibitors

Contact Info

Product

Resources

About