Carboxypeptidase M augments kinin B1 receptor signaling by conformational crosstalk and enhances endothelial nitric oxide output

Zhang, Xianming; Tan, Fulong; Brovkovych, Viktor; Zhang, Yongkang; Lowry, Jessica; Skidgel, Randal A.

doi:10.1515/hsz-2012-0290

Cited by 19 publications

(27 citation statements)

References 31 publications

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“…Concentration-Based on our previous work, CPM heterodimerizes with the B1R on the membrane, and this interaction enhances B1R signaling in two ways (29,34,35). First, the B2R agonists BK or KD can activate B1R signaling by binding to CPM as substrates, resulting in a conformational change in the B1R mediated by CPM/B1R protein-protein interactions and subsequent downstream activation of calcium or nitric oxide (NO) signaling (29,35).…”

Section: Cpm Enhances B1r Signaling At Submaximal Agonistmentioning

confidence: 99%

“…First, the B2R agonists BK or KD can activate B1R signaling by binding to CPM as substrates, resulting in a conformational change in the B1R mediated by CPM/B1R protein-protein interactions and subsequent downstream activation of calcium or nitric oxide (NO) signaling (29,35). Second, removal of the C-terminal Arg of BK or KD by CPM generates B1R agonists (e.g.…”

Section: Cpm Enhances B1r Signaling At Submaximal Agonistmentioning

confidence: 99%

“…Although several mammalian carboxypeptidases have the proper specificity to carry out this last step in vitro, fulfilling this role effectively in vivo would also depend on properties such as pH optimum, localization, access to kinin substrate, and proximity to the B1R (11,(27)(28)(29). CPM has ideal properties in this regard, being a GPI-anchored plasma membrane protein with a neutral pH optimum exhibiting a specificity for C-terminal Arg and the lowest K m for BK of the physiological substrates tested (1,8,12,30).…”

mentioning

confidence: 99%

“…CPM and B1Rs are co-localized in lipid raft domains and interact on the cell surface as evidenced by FRET analysis, cross-linking, and coimmunoprecipitation (34). Disruption of lipid rafts or the CPM/B1R interaction by CPM monoclonal antibody greatly reduced B1R signaling in response to administration of BK or KD (29,34). We initially attributed this to more efficient delivery of the CPM-cleaved products (i.e.…”

mentioning

confidence: 99%

“…B1R agonists) to the receptor. Although this is clearly an important component of the CPM effect, we recently discovered that the CPM/B1R interaction mediates a second, novel mechanism of B1R activation that results from substrate binding to CPM to cause a conformational change and allosteric activation of the B1R without generation of B1R agonist (29,35).…”

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confidence: 99%

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Carboxypeptidase M Is a Positive Allosteric Modulator of the Kinin B1 Receptor

Zhang¹,

Tan

Skidgel

2013

Journal of Biological Chemistry

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Background: Carboxypeptidase M (CPM) generates agonist for the kinin B1 receptor (B1R). Results: CPM binds to B1R on the cell membrane and allosterically increases B1R agonist affinity. Conclusion: CPM is a positive allosteric modulator of the B1R, thereby increasing receptor signaling. Significance: Interfering with CPM binding to B1R could be a novel approach to inhibit deleterious effects of B1R signaling in inflammation.

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Section: Cpm Enhances B1r Signaling At Submaximal Agonistmentioning

confidence: 99%

Section: Cpm Enhances B1r Signaling At Submaximal Agonistmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Carboxypeptidase M Is a Positive Allosteric Modulator of the Kinin B1 Receptor

Zhang¹,

Tan

Skidgel

2013

Journal of Biological Chemistry

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Bradykinin Promotes Cell Proliferation, Migration, Invasion, and Tumor Growth of Gastric Cancer Through ERK Signaling Pathway

Wang

Sun

Liu

et al. 2017

J of Cellular Biochemistry

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Bradykinin (BK) has been reported to be involved in the progression of diverse types of cancer. In the present study, we investigated the possible role of BK in cell proliferation, migration, invasion, and tumor growth of gastric cancer (GC). Cell proliferation was evaluated by MTT assays. Cell migration and invasion were assessed by Transwell assays. Tumor growth of nude mice was detected by establishing subcutaneous xenograft tumor model. Silencing of bradykinin B1 receptor (B1R) and the bradykinin B2 receptor (B2R) was performed by transfecting cells with si-B1R and si-B2R, respectively. The protein expression levels of phospho-ERK1/2 (p-ERK1/2), matrix metalloproteinase (MMP)-2, MMP-9, and E-Cadherin were examined by Western blot. Data revealed that BK promoted cell proliferation, migration, invasion, and the in vivo tumor growth of GC cells SGC-7901 and HGC-27. Furthermore, BK elevated the protein levels of p-ERK1/2, MMP-2, and MMP-9, but reduced E-Cadherin. In addition, by repressing B2R using si-B2R or inhibiting ERK signaling pathway using PD98059, BK-mediated promotion of cell proliferation, migration, and invasion and upregulation of p-ERK1/2, MMP-2/9, as well as downregulation of E-Cadherin were attenuated. Taken together, the present study demonstrated that BK promoted cell proliferation, migration, invasion, and tumor growth by binding to B2R via ERK signaling pathway. Our findings may provide promising options for the further treatment of GC. J. Cell. Biochem. 118: 4444-4453, 2017. © 2017 Wiley Periodicals, Inc.

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Tissue kallikrein protects rat hippocampal CA1 neurons against cerebral ischemia/reperfusion‐induced injury through the B2R‐Raf‐MEK1/2‐ERK1/2 pathway

Wang

Han

Cui

et al. 2014

J of Neuroscience Research

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We have documented that tissue kallikrein (TK) prevents neurons from hypoxia/reoxygenation injury through the B2R-ERK1/2 pathway and the antihypoxic function of TK through Homer1b/c-ERK1/2 signaling pathways. The present study investigates the molecular mechanisms of exogenous TK activation of the B2R-ERK1/2 pathway through the β-arrestin-2 assembled B2R-Raf-MEK1/2 signaling module in vivo. The cresyl violet staining results indicated that exogenous TK protected the rat hippocampal CA1 neurons against cerebral ischemia/reperfusion (I/R) injury. The immunoprecipitation (IP) and immunoblotting (IB) results revealed that exogenous TK upregulated the β-arrestin-2 assembled B2R-Raf-MEK1/2 signaling module and upregulated the phosphorylation of Raf (p-Raf), MEK1/2 (p-MEK1/2), and ERK1/2 (p-ERK1/2). Meanwhile, exogenous TK upregulated the expression of nuclear factor-κB (NF-κB), depressed the release of cytochrome c (Cyt c) and bax from mitochondria to the cytosol, and depressed the activation of caspase-3. Take together, our results suggest that exogenous TK attenuated the cerebral I/R induced rat hippocampal CA1 neurons injury through activating the β-arrestin-2 assembled B2R-Raf-MEK1/2 signaling module and that the activated B2R-Raf-MEK1/2 signaling module could upregulate the expression of NF-κB, decrease the release of cytochrome c and bax from mitochondria to the cytosol, and depress the activation of caspase-3.

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Carboxypeptidase M augments kinin B1 receptor signaling by conformational crosstalk and enhances endothelial nitric oxide output

Cited by 19 publications

References 31 publications

Carboxypeptidase M Is a Positive Allosteric Modulator of the Kinin B1 Receptor

Carboxypeptidase M Is a Positive Allosteric Modulator of the Kinin B1 Receptor

Bradykinin Promotes Cell Proliferation, Migration, Invasion, and Tumor Growth of Gastric Cancer Through ERK Signaling Pathway

Tissue kallikrein protects rat hippocampal CA1 neurons against cerebral ischemia/reperfusion‐induced injury through the B2R‐Raf‐MEK1/2‐ERK1/2 pathway

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