Mimicking phosphorylation at Ser‐48 strongly reduces surface expression of human macrophage scavenger receptor class A: implications on cell motility

Heider, Harald; Wintergerst, E. S.

doi:10.1016/s0014-5793(01)02819-8

Cited by 12 publications

(12 citation statements)

References 18 publications

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“…225 Substituting serine 48 in human SR-A1 by an aspartate demonstrated that surface expression of the mutated receptor was 13-fold decreased; the amount of cell-associated Texas red-labeled AcLDL in mutant receptor-expressing cells was almost threefold reduced; and the migration of mutant receptortransfected cells toward surfaces coated with Ox-LDL decreased by almost 60% compared to cells that were transfected with the wild-type receptor. 226 These observations indicate that phosphorylation of the cytoplasmic part of SR-A1 may help to modulate the residence time of macrophages in atherosclerotic lesions and again emphasize the importance of phosphorylation events in receptor upregulation and accumulation of modified lipids (Fig. 5).…”

Section: S I G N a L I N G E V E N T S A S S O C I A T E D W I T H mentioning

confidence: 66%

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Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Tiwari

Singh

Barthwal

2007

Medicinal Research Reviews

139

120

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Macrophages are central to the initiation and progression of atherosclerosis and thus can be very appropriate targets for therapy. Cell adhesion molecules mediating monocytes recruitment to the endothelium are attractive therapy targets and their inhibitors are in clinical trials. Macrophage scavenger receptors like SR-A and CD-36 mediate foam cell formation by facilitating the uptake of modified lipids. Peroxisome proliferator-activated receptors (PPAR), liver X receptor (LXR)-mediated signaling, mitogen-activated protein kinase (MAPK) induced phosphorylation events seem to play an important role in this phenomenon. Proteins affecting macrophage cholesterol metabolism and transport, including ATP-binding cassette (ABC) A1, ABCG1, acylCoA:cholesterol acyltransferase (ACAT), apolipoprotein A-1 (ApoA-1), neutral cholesteryl ester hydrolase (NCEH) also regulate foam cell formation and are being developed as therapeutic targets by many pharmaceutical companies. Macrophage proliferation and apoptosis are important events controlling inflammatory response, plaque vulnerability, and destabilization. Free cholesterol (FC) activates the macrophage endoplasmic reticulum (ER) stress pathway and apoptosis. Free radicals and nitric oxide also modulate macrophage foam cell formation and apoptosis. Various antioxidants like AGI-1067 and BO-653 are in clinical trials for atherosclerosis treatment. Macrophage matrix metalloproteinase's (MMP's) play a significant role in weakening and rupture of plaques. Efforts are on to develop isoform specific MMP inhibitor. CD-14, MMP-3, ABCA1, Toll-like receptor-4 (TLR-4), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), arachidonate lipoxygenase-15 (ALOX-15), and Connexin37 polymorphisms and macrophage dysfunction signify their importance in atherosclerosis. Deciphering the role of macrophages in regulating dyslipidemia and inflammation during atherosclerosis is important for developing them as therapeutic targets. ß 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 4, 483-544, 2008

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Section: S I G N a L I N G E V E N T S A S S O C I A T E D W I T H mentioning

confidence: 66%

“…5). 226 Since in JNK2 negative macrophages, SR-A is upregulated, it is possible that JNK2 negatively regulates a kinase, which has a role in phosphorylation-dependent SR-A upregulation. These evidences suggest that JNK mediates SR-A phosphorylation (Fig.…”

Section: S I G N a L I N G E V E N T S A S S O C I A T E D W I T H mentioning

confidence: 99%

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Tiwari

Singh

Barthwal

2007

Medicinal Research Reviews

139

120

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“…Furthermore, we also found that the EDXD motif, consisting of Glu 12 , Asp 13 , and Asp 15 , may not be necessary for endocytosis. The phosphorylation of serine residues proximal to the membrane has also been demonstrated to be necessary for SR-A internalization (19,21), indicating the complicated nature of regulation of receptor internalization.…”

Section: Discussionmentioning

confidence: 99%

The Microtubule-binding Protein Hook3 Interacts with a Cytoplasmic Domain of Scavenger Receptor A

Sano

Ishino

Krämer

et al. 2007

Journal of Biological Chemistry

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The class A scavenger receptor (SR-A, and Asp 15 in the human SR-A cytoplasmic domain. By transfecting small interfering RNA targeting Hook3, total and surface expression, receptor-mediated ligand uptake and protein stability of SR-A were significantly promoted, whereas the protein synthesis and maturation were not altered. We propose for the first time that Hook3 may participate in the turnover of the endocytosed scavenger receptor.

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“…In addition, phosphorylation of Ser48 was reported to act as a key mediator for internalization. 23 However, the influence of the heterogeneity in SR-A cytoplasmic domain on mediating uptake of ligand into cell would not be neglected. For example, a significant difference in the structure of cytoplasmic domain exists between human and murine SR-A, The murine SR-A has 5 more amino acid residues in its cytoplasmic domain than does human SR-A, and their homology is 76% (blast in NCBI).…”

Section: Discussionmentioning

confidence: 99%

The Di-Leucine Motif Contributes to Class A Scavenger Receptor-Mediated Internalization of Acetylated Lipoproteins

Chen

Wang²,

Ben³

et al. 2006

ATVB

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Objective-The di-leucine motif exists in the intracellular domains of certain cell surface receptors, participating in the receptor-mediated endocytosis. The present study was aimed at determining the role of the di-leucine motif in class A scavenger receptor (SR-A)-mediated ligand endocytosis. Methods and Results-cDNA coding for a mutant (SR-A mutant N3132LM) with deletion of the di-leucine structure was transfected into Chinese hamster ovary (CHO) cells. Compared with wild-type SR-A-expressing cells, the cells expressing the SR-A mutant N3132LM showed a significant decrease in uptake but almost no change in binding of the SR-A ligand acetylated low-density lipoprotein (AcLDL). Western blot analysis revealed coimmunoprecipitation of SR-A mutant and clathrin from the lysates of the mutant but not wild-type CHO cells, suggesting that AcLDL-bound SR-A mutant N3132LM is associated with the clathrin-coated pit of cellular membrane. Removal of the first 27 amino acid residues from the SR-A N-terminus further reduced AcLDL uptake by the cells with the di-leucine motif mutation. Conclusions-The

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Mimicking phosphorylation at Ser‐48 strongly reduces surface expression of human macrophage scavenger receptor class A: implications on cell motility

Cited by 12 publications

References 18 publications

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

The Microtubule-binding Protein Hook3 Interacts with a Cytoplasmic Domain of Scavenger Receptor A

The Di-Leucine Motif Contributes to Class A Scavenger Receptor-Mediated Internalization of Acetylated Lipoproteins

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