M. Amin Arnaout

Last updated
M. Amin Arnaout
Aarnaout.png
Born
Sidon, Lebanon
Nationality American
Alma mater American University of Beirut
Known for Cell adhesion, Integrins, Inflammation
AwardsKuwait Prize (2017)
Homer W. Smith Award (2018)
Visionary Award in Nephrology (2023)
Scientific career
Fields Biology, Immunology, Medicine, Nephrology, Structural Biology
Institutions Massachusetts General Hospital
Harvard Medical School
Children's Hospital Boston
Johns Hopkins University
Academic advisorsHarvey R. Colten
Website www.massgeneral.org

M. Amin Arnaout is a Lebanese physician-scientist and nephrologist best known for seminal discoveries in the biology and structure of integrin receptors. He is Professor of Medicine at Harvard Medical School and Physician, former Chief of Nephrology, and Director of the Leukocyte Biology and Inflammation Laboratory at the Massachusetts General Hospital (MGH).

Research

Arnaout’s research on the biology and structure of integrins has led to scientific observations that span the entire spectrum from gene discovery to 3-dimensional protein structure to clinical translation. He described an inherited deficiency in leukocyte adhesion in a lead article in the New England Journal of Medicine; [1] defined the biochemical and molecular basis of this disease, which he traced to a deficiency in a family of leukocyte surface glycoprotein receptors, now known as leukocyte β2 integrins [2] [3] and elucidated the role of these cell adhesion molecules in the immune system. [4] He was also the first to determine the crystal structures of integrins. [5] [6] [7] [8] [9] His molecular and structural studies in integrins were instrumental in understanding the processes involved in organ development, maintenance of organ architecture and homeostasis in the adult, cancer growth and metastasis, and the response of organs to acute and chronic inflammatory or autoimmune injury. For example, in the kidney, integrins are now known to be critical in maintaining the kidney filtration barrier thus preventing loss of blood and proteins in the urine, [10] and also mediate the respiratory distress observed in kidney failure patients when hemodialyzed using cuprophane membranes. [11] Arnaout's current research aims at translating his discoveries in integrin biology and structure into novel and safer drugs for treating inflammatory, thrombotic, fibrotic and autoimmune diseases and cancer, using structure-based drug design. [12] [13] [14] [15] [16]

His research on cell adhesion and integrins has been described as "concomitantly advancing the field one enormous stride," [17] as "one of those spectacular results that will change a field", [18] a "MIDAS touch to cell signaling" [19] and has been featured in the lay press including the New York Times. [20] His two research papers published in the journal Science are the two most quoted in the integrin field for the past 20 years.

Arnaout was the first to show that C3 nephritic factor is an autoantibody to the complement C3bBb convertase that activates the alternative complement pathway, [21] [22] a finding that suggested the potential of B cell or complement C5 depletion as adjunct therapies in certain forms of kidney inflammation. He was also the first to identify the antigen targeted by autoantibodies in patients with systemic vasculitis, [23] which formed the basis for a routinely used diagnostic assay. He was the first to show that polycystin-1, one of two gene products mutated in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), is required for the structural integrity of blood vessels, [24] indicating that the early onset of high blood pressure and presence of vascular aneurysms in ADPKD is caused by a primary defect in vascular polycystin-1. In collaborative studies, he also showed that polycystin-2, the other gene product defective in ADPKD, is a TRP-like calcium channel, [25] providing new insights into the molecular pathogenesis of ADPKD.

Related Research Articles

<span class="mw-page-title-main">Integrin</span> Instance of a defined set in Homo sapiens with Reactome ID (R-HSA-374573)

Integrins are transmembrane receptors that help cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, organization of the intracellular cytoskeleton, and movement of new receptors to the cell membrane. The presence of integrins allows rapid and flexible responses to events at the cell surface.

<span class="mw-page-title-main">Cell adhesion</span> Process of cell attachment

Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.

<span class="mw-page-title-main">Basement membrane</span> Thin fibrous layer between the cells and the adjacent connective tissue in animals

The basement membrane, also known as base membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between epithelial tissues including mesothelium and endothelium, and the underlying connective tissue.

<span class="mw-page-title-main">CD31</span> Mammalian protein found in Homo sapiens

Platelet endothelial cell adhesion molecule (PECAM-1) also known as cluster of differentiation 31 (CD31) is a protein that in humans is encoded by the PECAM1 gene found on chromosome17q23.3. PECAM-1 plays a key role in removing aged neutrophils from the body.

<span class="mw-page-title-main">ICAM-1</span> Mammalian protein found in Homo sapiens

ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor for entry into respiratory epithelium.

<span class="mw-page-title-main">Integrin alpha X</span> Mammalian protein found in Homo sapiens

CD11c, also known as Integrin, alpha X (ITGAX), is a gene that encodes for CD11c.

<span class="mw-page-title-main">Integrin alpha L</span> Mammalian protein found in Homo sapiens

Integrin, alpha L , also known as ITGAL, is a protein that in humans is encoded by the ITGAL gene. CD11a functions in the immune system. It is involved in cellular adhesion and costimulatory signaling. It is the target of the drug efalizumab.

<span class="mw-page-title-main">Integrin alpha M</span> Mammalian protein found in Homo sapiens

Integrin alpha M (ITGAM) is one protein subunit that forms heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3). ITGAM is also known as CR3A, and cluster of differentiation molecule 11B (CD11B). The second chain of αMβ2 is the common integrin β2 subunit known as CD18, and integrin αMβ2 thus belongs to the β2 subfamily integrins.

<span class="mw-page-title-main">Integrin beta 2</span> Mammalian protein found in Homo sapiens

In molecular biology, CD18 is an integrin beta chain protein that is encoded by the ITGB2 gene in humans. Upon binding with one of a number of alpha chains, CD18 is capable of forming multiple heterodimers, which play significant roles in cellular adhesion and cell surface signaling, as well as important roles in immune responses. CD18 also exists in soluble, ligand binding forms. Deficiencies in CD18 expression can lead to adhesion defects in circulating white blood cells in humans, reducing the immune system's ability to fight off foreign invaders.

<span class="mw-page-title-main">Integrin beta 1</span> Mammalian protein found in Homo sapiens

Integrin beta-1 (ITGB1), also known as CD29, is a cell surface receptor that in humans is encoded by the ITGB1 gene. This integrin associates with integrin alpha 1 and integrin alpha 2 to form integrin complexes which function as collagen receptors. It also forms dimers with integrin alpha 3 to form integrin receptors for netrin 1 and reelin. These and other integrin beta 1 complexes have been historically known as very late activation (VLA) antigens.

Macrophage-1 antigen is a complement receptor ("CR3") consisting of CD11b and CD18.

<span class="mw-page-title-main">Leukocyte extravasation</span>

Leukocyte extravasation is the movement of leukocytes out of the circulatory system and towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes. Monocytes also use this process in the absence of infection or tissue damage during their development into macrophages.

<span class="mw-page-title-main">FGR (gene)</span> Protein-coding gene in the species Homo sapiens

Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog, also known as FGR, is a protein which in humans is encoded by the FGR gene.

<span class="mw-page-title-main">Laminin, alpha 5</span> Protein-coding gene in the species Homo sapiens

Laminin subunit alpha-5 is a protein that in humans is encoded by the LAMA5 gene.

<span class="mw-page-title-main">F11 receptor</span> Protein-coding gene in the species Homo sapiens

Junctional adhesion molecule A is a protein that in humans is encoded by the F11R gene. It has also been designated as CD321.

<span class="mw-page-title-main">Integrin beta 7</span>

Integrin beta-7 is an integrin protein that in humans is encoded by the ITGB7 gene. It can pair with ITGA4 (CD49d) to form the heterodimeric integrin receptor α4β7, or with ITGAE (CD103) to form αEβ7.

<span class="mw-page-title-main">CEACAM8</span> Mammalian protein found in Homo sapiens

Carcinoembryonic antigen-related cell adhesion molecule 8 (CEACAM8) also known as CD66b, is a member of the carcinoembryonic antigen (CEA) gene family. Its main function is cell adhesion, cell migration, and pathogen binding.

<span class="mw-page-title-main">Integrin alpha D</span> Protein-coding gene in the species Homo sapiens

Integrin alpha-D is a protein that in humans is encoded by the ITGAD gene.

The following outline is provided as an overview of and topical guide to immunology:

<span class="mw-page-title-main">FERMT3</span> Protein-coding gene in the species Homo sapiens

Fermitin family homolog 3) (FERMT3), also known as kindlin-3 (KIND3), MIG2-like protein (MIG2B), or unc-112-related protein 2 (URP2) is a protein that in humans is encoded by the FERMT3 gene. The kindlin family of proteins, member of the B4.1 superfamily, comprises three conserved protein homologues, kindlin 1, 2, and 3. They each contain a bipartite FERM domain comprising four subdomains F0, F1, F2, and F3 that show homology with the FERM head (H) domain of the cytoskeletal Talin protein. Kindlins have been linked to Kindler syndrome, leukocyte adhesion deficiency, cancer and other acquired human diseases. They are essential in the organisation of focal adhesions that mediate cell-extracellular matrix junctions and are involved in other cellular compartments that control cell-cell contacts and nucleus functioning. Therefore, they are responsible for cell to cell crosstalk via cell-cell contacts and integrin mediated cell adhesion through focal adhesion proteins and as specialised adhesion structures of hematopoietic cells they are also present in podosome's F actin surrounding ring structure. Isoform 2 may act as a repressor of NF-kappa-B and apoptosis

References

  1. ↑ N Engl J Med. 1982 Mar 25;306(12):693-9
  2. ↑ J Clin Invest. 1984 Jan;73(1):153-9
  3. ↑ J Clin Invest. 1984 Oct;74(4):1291-300
  4. ↑ Immunol Rev. 1990 Apr;114:145-80
  5. ↑ Cell. 1993 Mar 26;72(6):857-67
  6. ↑ Cell. 1995 Feb 24;80(4):631-8
  7. ↑ Science. 2001 Oct 12;294(5541):339-45
  8. ↑ Science. 2002 Apr 5;296(5565):151-5
  9. ↑ Current Biology. 2002 May 14;12(10):R340-2
  10. ↑ N Engl J Med. 2013 Dec 19;369(25):2416-23
  11. ↑ N Engl J Med. 1985 Feb 21;312(8):457-62
  12. ↑ J Immunol. 2011 Dec 15;187(12):6393-401
  13. ↑ Nat Struct Mol Biol. 2014 Apr;21(4):383-8
  14. ↑ Nature Communications 2017 Jan 10; 8:13899
  15. ↑ Nature Communications 2020 Jan 21;11(1):398
  16. ↑ Nature Communications 2023 Jul 13;14(1):4168
  17. ↑ Science 2001 Oct 12;294: 316-7
  18. ↑ Science 2001 Sep 7;293:1743-1746
  19. ↑ Nature Reviews Mol Cell Biology 2002 May; 3:313
  20. ↑ "Infection Fighter Discovered". The New York Times. 26 March 1993.
  21. ↑ J Immunol. 1977 Oct;119(4):1316-20
  22. ↑ N Engl J Med. 1977 Jul 21;297(3):144-5
  23. ↑ Blood. 1989 Nov 1;74(6):1888-93
  24. ↑ Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1731-6
  25. ↑ Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1182-7
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