Regulated cleavage-secretion of the membrane-bound angiotensin-converting enzyme.

Ramchandran, Ramaswamy; Sen, Ganes C.; Misono, Kunio S.; Sen, Indira

doi:10.1016/s0021-9258(17)42144-2

Cited by 95 publications

(31 citation statements)

References 29 publications

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“…The proteolysis of ACE ( 47), IL-6 receptor (46), and the TNF receptor (45), like that of L-sdectin, appears resistant to a broad panel of protease inhibitors. Interestingly, rabbit ACE is deaved between an arginine and a serine residue (47), and B-APP (42,43), is cleaved between a lysine and a leucine residue. These cleavage sites are homologous to the lysine and serine residues at the Pl and Pl' positions, respectively, of the L-selectin cleavage site.…”

Section: Discussionmentioning

confidence: 99%

“…These cleavage sites are homologous to the lysine and serine residues at the Pl and Pl' positions, respectively, of the L-selectin cleavage site. Also, like L-selectin, these other receptors are cleaved when expressed in COS or Chinese hamster ovary cells, and the cleavage specificity is retained (42,43,46,47). Despite the apparent similarity of these cleavage sites, the cleavage regions of/3-APP, ACE, and L-selectin can be mutated without dramatic effect on the efficiency of proteolysis.…”

Section: Discussionmentioning

confidence: 99%

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Mutational analysis of the membrane-proximal cleavage site of L-selectin: relaxed sequence specificity surrounding the cleavage site.

Kahn

Kishimoto

1995

The Journal of Experimental Medicine

124

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SummaryL-selectin expression is regulated in part by membrane-proximal cleavage from the cell surface of leukocytes and L-selectin-transfected cells. The downregulation of L-selectin from the surface of neutrophils is speculated to be a process involved in the adhesion cascade leading to neutrophil recruitment to sites of inflammation. We previously reported that L-selectin is cleaved between Lys321 and Ser322 in a region that links the second short consensus repeat (SCR) and the transmembrane domain. We demonstrate that replacing this cleavage domain of L-selectin with the corresponding region of E-selectin prevents L-selectin shedding, as judged by inhibiting the generation of the 68-kD soluble and 6-kD transmembrane cleavage products of L-selectin. Unexpectedly, we found that point mutations of the cleavage site, as well as mutations of multiple conserved amino acids within the cleavage domain, do not significantly affect L-sdectin shedding. However, short deletions of four or five amino acids in the L-selectin cleavage domain inhibit L-selectin downregulation. Mutations that appeared to inhibit L-selectin shedding resulted in higher levels of ceU surface expression, consistent with a lack of apparent proteolysis from the cell membrane. One deletion mutant, I327AN332, retains the native cleavage site yet inhibits L-selectin proteolysis as well. Restoring the amino acids deleted between I327 and N332 with five alanine residues restores L-selectin proteolysis. Thus, the proteolytic processing of L-selectin appears to have a relaxed sequence specificity at the cleavage site, and it may depend on the physical length or other secondary structural characteristics of the cleavage domain.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mutational analysis of the membrane-proximal cleavage site of L-selectin: relaxed sequence specificity surrounding the cleavage site.

Kahn

Kishimoto

1995

The Journal of Experimental Medicine

124

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“…1,2 ACE is bound to endothelial surface membrane by an anchor peptide, which could be cleaved by ACE secretase to form a soluble enzyme called serum ACE. 3…”

Section: Introductionmentioning

confidence: 99%

Gender difference of serum angiotensin-converting enzyme (ACE) activity in DD genotype of ACE insertion/deletion polymorphism in elderly Chinese

Zhang

Cheng

Tang

et al. 2013

J Renin Angiotensin Aldosterone Syst

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Introduction: In this study we investigated the gender difference of serum angiotensin-converting enzyme (ACE) activity in a population of Hong Kong-dwelling elderly Chinese. Materials and methods: A total of 1767 (843 male, 924 female) Hong Kong-dwelling elderly Chinese were recruited. ACE I/D genotypes were identified by polymerase chain reaction amplification and serum ACE activity was determined using a commercially available kinetic kit. ACE I/D genotype distribution was compared by chi-square test, the correlation between ACE I/D polymorphism and serum ACE activity was analysed by ANOVA test and gender difference of serum ACE activity of different genotypes was compared by independent sample t-test. Results: No statistically significant difference of genotype distribution between male and female subjects was found. Serum ACE activity was significantly correlated with ACE genotype. Overall, there was no gender difference of serum ACE activity; however, when sub-grouping the subjects by ACE I/D genotype, male subjects with DD genotype had higher serum ACE activity than female subjects with DD genotype. Conclusions: No significant gender difference of genotype distribution was found in elderly Chinese. Serum ACE activity was significantly correlated with ACE I/D polymorphism in elderly Chinese. Male subjects with DD genotype had higher serum ACE activity than female subjects with DD genotype.

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“…Cleavage of membrane protein ectodomains is often a regulated process. The extracellular domains of proTGF-ot (Pandiella and Massagu6, 1991a), kit ligand (Huang et al, 1992), colony-stimulating factor 1 (CSF-1) (Stein and Rettenmier, 1991), CSF-1 receptor (Downing et al, 1989), tumor necrosis factor ct (TNF-ot) receptors (Porteu and Nathan, 1990;Porteu et al, 1991), IL-6 receptor (Serra-Pages et al, 1994, LAR transmembrane protein tyrosine phosphatase (Miillberg et al, 1992), ~APP protein (Buxbaum et al, 1990), the cell adhesion molecule L-selectin (Kishimoto et al, 1989;Kahn et al, 1994), and angiotensin-converting enzyme (Ramchandrarn et al, 1994) are released at a slow rate in resting cells but are cleaved minutes after adding certain agonists including protein kinase C activators, calcium ionophores, and serum factors (Pandiella and Massagu6, 1991b;Buxbaum et al, 1994).…”

mentioning

confidence: 99%

Transforming growth factor-alpha and beta-amyloid precursor protein share a secretory mechanism.

Arribas

Massagué

1995

The Journal of Cell Biology

141

104

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Abstract. Cleavage and release of membrane protein ectodomains, a regulated process that affects many cell surface proteins, remains largely uncharacterized. To investigate whether cell surface proteins are cleaved through a shared mechanism or through multiple independent mechanisms, we mutagenized Chinese hamster ovary (CHO) cells and selected clones that were unable to cleave membrane-anchored transforming growth factor o~ (TGF-a). The defect in TGF-a cleavage in these clones is most apparent upon cell treatment with the protein kinase C (PKC) activator PMA, which stimulates TGF-ct cleavage in wild-type cells. The mutant clones do not have defects in TFG-ct expression, transport to the cell surface or turnover. Concomitant with the loss of TGF-ot cleavage, these clones have lost the ability to cleave many structurally unrelated membrane proteins in response to PMA. These proteins include ~-amyloid precursor protein (/3-APP), whose cleavage into a secreted form avoids conversion into the amyloidogenic peptide A/~, and a group of cell surface proteins whose release into the medium is stimulated by PMA in wild type CHO cells but not in mutants. The mutations prevent cleavage by PKC-dependent as well as PKC-independent mechanisms, and thus affect an essential component that functions downstream of these various signaling mechanisms. We propose that regulated cleavage and secretion of membrane protein ectodomains is mediated by a common system whose components respond to multiple activators and act on susceptible proteins of diverse structure and function.

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Regulated cleavage-secretion of the membrane-bound angiotensin-converting enzyme.

Cited by 95 publications

References 29 publications

Mutational analysis of the membrane-proximal cleavage site of L-selectin: relaxed sequence specificity surrounding the cleavage site.

Mutational analysis of the membrane-proximal cleavage site of L-selectin: relaxed sequence specificity surrounding the cleavage site.

Gender difference of serum angiotensin-converting enzyme (ACE) activity in DD genotype of ACE insertion/deletion polymorphism in elderly Chinese

Transforming growth factor-alpha and beta-amyloid precursor protein share a secretory mechanism.

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