SVEP1 is an Endogenous Ligand for the Orphan Receptor PEAR1

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Feb 15

PMID 36792666

Authors

Jared S Elenbaas

Upasana Pudupakkam

Katrina J Ashworth

Chul Joo Kang

Ved Patel

Katherine Santana

In-Hyuk Jung

Paul C Lee

Kendall H Burks

Junedh M Amrute

Robert P Mecham

Carmen M Halabi

Arturo Alisio

Jorge Di Paola

Nathan O Stitziel

Affiliations

Soon will be listed here.

Abstract

Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that causally promotes vascular disease and associates with platelet reactivity in humans. Here, using a human genomic and proteomic approach, we identify a high affinity, disease-relevant, and potentially targetable interaction between SVEP1 and the orphan receptor Platelet and Endothelial Aggregation Receptor 1 (PEAR1). This interaction promotes PEAR1 phosphorylation and disease associated AKT/mTOR signaling in vascular cells and platelets. Mice lacking SVEP1 have reduced platelet activation, and exogenous SVEP1 induces PEAR1-dependent activation of platelets. SVEP1 and PEAR1 causally and concordantly relate to platelet phenotypes and cardiovascular disease in humans, as determined by Mendelian Randomization. Targeting this receptor-ligand interaction may be a viable therapeutic strategy to treat or prevent cardiovascular and thrombotic disease.

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References

Li P, Halabi C, Stewart R, Butler A, Brown B, Xia X . Sodium-activated potassium channels moderate excitability in vascular smooth muscle. J Physiol. 2019; 597(20):5093-5108. PMC: 6800802. DOI: 10.1113/JP278279. View

Letunic I, Khedkar S, Bork P . SMART: recent updates, new developments and status in 2020. Nucleic Acids Res. 2020; 49(D1):D458-D460. PMC: 7778883. DOI: 10.1093/nar/gkaa937. View

Woulfe D . Akt signaling in platelets and thrombosis. Expert Rev Hematol. 2010; 3(1):81-91. PMC: 2844717. DOI: 10.1586/ehm.09.75. View

Johnson A, Yanek L, Chen M, Faraday N, Larson M, Tofler G . Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists. Nat Genet. 2010; 42(7):608-13. PMC: 3057573. DOI: 10.1038/ng.604. View

Cadena D, Gill G . Receptor tyrosine kinases. FASEB J. 1992; 6(6):2332-7. DOI: 10.1096/fasebj.6.6.1312047. View

Vandenbriele C, Sun Y, Criel M, Cludts K, van Kerckhoven S, Izzi B . Dextran sulfate triggers platelet aggregation via direct activation of PEAR1. Platelets. 2015; 27(4):365-72. DOI: 10.3109/09537104.2015.1111321. View

Wu H, Bellmunt E, Scheib J, Venegas V, Burkert C, Reichardt L . Glial precursors clear sensory neuron corpses during development via Jedi-1, an engulfment receptor. Nat Neurosci. 2009; 12(12):1534-41. PMC: 2834222. DOI: 10.1038/nn.2446. View

Man J, Beckman J, Jaffe I . Sex as a Biological Variable in Atherosclerosis. Circ Res. 2020; 126(9):1297-1319. PMC: 7185045. DOI: 10.1161/CIRCRESAHA.120.315930. View

Branon T, Bosch J, Sanchez A, Udeshi N, Svinkina T, Carr S . Efficient proximity labeling in living cells and organisms with TurboID. Nat Biotechnol. 2018; 36(9):880-887. PMC: 6126969. DOI: 10.1038/nbt.4201. View

10.

Jung I, Elenbaas J, Burks K, Amrute J, Xiangyu Z, Alisio A . Vascular smooth muscle- and myeloid cell-derived integrin α9β1 does not directly mediate the development of atherosclerosis in mice. Atherosclerosis. 2022; 360():15-20. PMC: 9615102. DOI: 10.1016/j.atherosclerosis.2022.09.015. View

11.

Stitziel N, Stirrups K, Masca N, Erdmann J, Ferrario P, Konig I . Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. N Engl J Med. 2016; 374(12):1134-44. PMC: 4850838. DOI: 10.1056/NEJMoa1507652. View

12.

Wirka R, Wagh D, Paik D, Pjanic M, Nguyen T, Miller C . Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis. Nat Med. 2019; 25(8):1280-1289. PMC: 7274198. DOI: 10.1038/s41591-019-0512-5. View

13.

Kirchhausen T, Macia E, Pelish H . Use of dynasore, the small molecule inhibitor of dynamin, in the regulation of endocytosis. Methods Enzymol. 2008; 438:77-93. PMC: 2796620. DOI: 10.1016/S0076-6879(07)38006-3. View

14.

Sun B, Maranville J, Peters J, Stacey D, Staley J, Blackshaw J . Genomic atlas of the human plasma proteome. Nature. 2018; 558(7708):73-79. PMC: 6697541. DOI: 10.1038/s41586-018-0175-2. View

15.

Erde J, Ogorzalek Loo R, Loo J . Improving Proteome Coverage and Sample Recovery with Enhanced FASP (eFASP) for Quantitative Proteomic Experiments. Methods Mol Biol. 2017; 1550:11-18. PMC: 6205185. DOI: 10.1007/978-1-4939-6747-6_2. View

16.

Tikhonova A, Dolgalev I, Hu H, Sivaraj K, Hoxha E, Cuesta-Dominguez A . The bone marrow microenvironment at single-cell resolution. Nature. 2019; 569(7755):222-228. PMC: 6607432. DOI: 10.1038/s41586-019-1104-8. View

17.

Karpanen T, Padberg Y, van de Pavert S, Dierkes C, Morooka N, Peterson-Maduro J . An Evolutionarily Conserved Role for Polydom/Svep1 During Lymphatic Vessel Formation. Circ Res. 2017; 120(8):1263-1275. PMC: 5389596. DOI: 10.1161/CIRCRESAHA.116.308813. View

18.

Weisbrod R, Shiang T, Al Sayah L, Fry J, Bajpai S, Reinhart-King C . Arterial stiffening precedes systolic hypertension in diet-induced obesity. Hypertension. 2013; 62(6):1105-10. PMC: 3951434. DOI: 10.1161/HYPERTENSIONAHA.113.01744. View

19.

Scheib J, Sullivan C, Carter B . Jedi-1 and MEGF10 signal engulfment of apoptotic neurons through the tyrosine kinase Syk. J Neurosci. 2012; 32(38):13022-31. PMC: 3464495. DOI: 10.1523/JNEUROSCI.6350-11.2012. View

20.

Perkins D, Pappin D, Creasy D, Cottrell J . Probability-based protein identification by searching sequence databases using mass spectrometry data. Electrophoresis. 1999; 20(18):3551-67. DOI: 10.1002/(SICI)1522-2683(19991201)20:18<3551::AID-ELPS3551>3.0.CO;2-2. View