Internalization of Proprotein Convertase PC7 from Plasma Membrane Is Mediated by a Novel Motif

Declercq, Jeroen; Meulemans, Sandra; Plets, Evelyn; Creemers, John W.M.

doi:10.1074/jbc.m111.306407

Cited by 22 publications

(29 citation statements)

References 36 publications

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“…A similar defect in Kremen1 internalization was also observed after treatment of cells with pitstop 2, a small molecule inhibitor of clathrin-mediated endocytosis or using Dynasore [35]. Pitstop 2 has been shown to inhibit the internalization of subtilisin-like proprotein convertase family member proprotein convertase 7 (PC7) from the cell surface by blocking the clathrin terminal domain binding site [42]. These data support the previously reported studies that the internalization of Kremen1 requires clathrin and AP-2 [43].…”

Section: Discussionsupporting

confidence: 87%

High-Affinity Dkk1 Receptor Kremen1 Is Internalized by Clathrin-Mediated Endocytosis

et al. 2012

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Kremens are high-affinity receptors for Dickkopf 1 (Dkk1) and regulate the Wnt/β-catenin signaling pathway by down-regulating the low-density lipoprotein receptor-related protein 6 (LRP6). Dkk1 competes with Wnt for binding to LRP6; binding of Dkk1 inhibits canonical signaling through formation of a ternary complex with Kremen. The majority of down-regulated clathrin-mediated endocytic receptors contain short conserved regions that recognize tyrosine or dileucine sorting motifs. In this study, we found that Kremen1 is internalized from the cell surface in a clathrin-dependent manner. Kremen1 contains an atypical dileucine motif with the sequence DXXXLV. Mutation of LV to AA in this motif blocked Kremen1 internalization; as reported previously for other proteins, the aspartic acid residue in Kremen1 is not critical. Inhibition of expression of the adaptor protein 2 (AP-2) or inhibition of clathrin by pitstop 2 also blocked Kremen1 internalization. The novel amino acid sequence identified in Kremen1 is similar to the motif previously identified in hydra, yeast, and other organisms known to signal from the trans-Golgi network to the endosomal compartment.

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Section: Discussionsupporting

confidence: 87%

High-Affinity Dkk1 Receptor Kremen1 Is Internalized by Clathrin-Mediated Endocytosis

et al. 2012

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“…PCSK7 has previously been implicated as a mediator of adipogenesis 39 and in the processing of VEGF-D, a critical step for binding of the angiogenic receptor VEGFR-2. 40 Furthermore, recent data show that internalization of PCSK7 from the plasma membrane is mediated by clathrin-coated vesicles, 41 which are also implicated in the internalization of other cellular receptors such as the LDL receptor and various scavenger receptors. Although the physiologic role of PCSK7 is not clearly understood, it is plausible that PCSK7 could be involved in the processing of LDL and/or scavenger receptors, thereby modulating circulating lipid levels.…”

Section: Discussionmentioning

confidence: 99%

Small Dense Low-Density Lipoprotein-Cholesterol Concentrations Predict Risk for Coronary Heart Disease

Hoogeveen

Gaubatz

Sun

et al. 2014

ATVB

428

347

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Objective To investigate the relationship between plasma levels of small dense low-density lipoprotein cholesterol (sdLDL-C) and risk for incident coronary heart disease (CHD) in a prospective study among Atherosclerosis Risk in Communities (ARIC) study participants. Approach and Results Plasma sdLDL-C was measured in 11,419 men and women of the biracial ARIC study using a newly developed homogeneous assay. A proportional hazards model was used to examine the relationship between sdLDL-C, vascular risk factors, and risk for CHD events (n=1,158) over a period of ≈11 years. Plasma sdLDL-C levels were strongly correlated with an atherogenic lipid profile and were higher in diabetics than nondiabetics (49.6 vs. 42.3 mg/dL, p<0.0001). In a model that included established risk factors, sdLDL-C was associated with incident CHD with a hazard ratio (HR) of 1.51 (95%CI: 1.21–1.88) for the highest versus the lowest quartile, respectively. Even in individuals considered to be at low cardiovascular risk based on their LDL-C levels, sdLDL-C predicted risk for incident CHD (HR 1.61; 95% CI 1.04–2.49). Genome-wide association analyses identified genetic variants in 8 loci associated with sdLDL-C levels. These loci were in or close to genes previously associated with risk for CHD. We discovered 1 novel locus, PCSK7, for which genetic variation was significantly associated with sdLDL-C and other lipid factors. Conclusions sdLDL-C was associated with incident CHD in ARIC study participants. The novel association of genetic variants in PCSK7 with sdLDL-C and other lipid traits may provide new insights into the role of this gene in lipid metabolism.

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“…exerts its function mainly in the trans-Golgi network and on the cell surface (13,14). Importantly, previous biochemical studies indicate that PCSK7 operates often redundantly with other PCSKs, especially FURIN.…”

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confidence: 99%

Proprotein Convertase Subtilisin/Kexin Type 7 (PCSK7) Is Essential for the Zebrafish Development and Bioavailability of Transforming Growth Factor β1a (TGFβ1a)

Turpeinen

Oksanen²,

Kivinen

et al. 2013

Journal of Biological Chemistry

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Background:The in vivo importance of PCSK7 in the vertebrates is currently poorly understood. Results: Inhibiting PCSK7 in zebrafish results in various developmental defects and dysregulation of gene expressions. Conclusion: PCSK7 is essential for zebrafish development and regulates the expression and proteolytic cleavage of TGF␤1a. Significance: PCSK inhibitors are considered future therapeutics for human diseases; understanding the biological role of PCSK7 is therefore critical.

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Internalization of Proprotein Convertase PC7 from Plasma Membrane Is Mediated by a Novel Motif

Cited by 22 publications

References 36 publications

High-Affinity Dkk1 Receptor Kremen1 Is Internalized by Clathrin-Mediated Endocytosis

High-Affinity Dkk1 Receptor Kremen1 Is Internalized by Clathrin-Mediated Endocytosis

Small Dense Low-Density Lipoprotein-Cholesterol Concentrations Predict Risk for Coronary Heart Disease

Proprotein Convertase Subtilisin/Kexin Type 7 (PCSK7) Is Essential for the Zebrafish Development and Bioavailability of Transforming Growth Factor β1a (TGFβ1a)

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