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ANGPT1

Official Full Name
angiopoietin 1
Organism
Homo sapiens
GeneID
284
Background
This gene encodes a secreted glycoprotein that belongs to the angiopoietin family. Members of this family play important roles in vascular development and angiogenesis. All angiopoietins bind with similar affinity to an endothelial cell-specific tyrosine-protein kinase receptor. The protein encoded by this gene is a secreted glycoprotein that activates the receptor by inducing its tyrosine phosphorylation. It plays a critical role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme and inhibits endothelial permeability. The protein also contributes to blood vessel maturation and stability, and may be involved in early development of the heart. Mutations in this gene are associated with hereditary angioedema. [provided by RefSeq, Aug 2020]
Synonyms
AGP1; AGPT; ANG1; HAE5; AGPT-1;
Bio Chemical Class
Fibrinogen protein
Protein Sequence
MTVFLSFAFLAAILTHIGCSNQRRSPENSGRRYNRIQHGQCAYTFILPEHDGNCRESTTDQYNTNALQRDAPHVEPDFSSQKLQHLEHVMENYTQWLQKLENYIVENMKSEMAQIQQNAVQNHTATMLEIGTSLLSQTAEQTRKLTDVETQVLNQTSRLEIQLLENSLSTYKLEKQLLQQTNEILKIHEKNSLLEHKILEMEGKHKEELDTLKEEKENLQGLVTRQTYIIQELEKQLNRATTNNSVLQKQQLELMDTVHNLVNLCTKEGVLLKGGKREEEKPFRDCADVYQAGFNKSGIYTIYINNMPEPKKVFCNMDVNGGGWTVIQHREDGSLDFQRGWKEYKMGFGNPSGEYWLGNEFIFAITSQRQYMLRIELMDWEGNRAYSQYDRFHIGNEKQNYRLYLKGHTGTAGKQSSLILHGADFSTKDADNDNCMCKCALMLTGGWWFDACGPSNLNGMFYTAGQNHGKLNGIKWHYFKGPSYSLRSTTMMIRPLDF
Open
Disease
Alzheimer disease, Asthma, Breast cancer, General pain disorder, Ovarian cancer, Renal cell carcinoma, Sexual dysfunction, Solid tumour/cancer
Approved Drug
0
Clinical Trial Drug
3 +
Discontinued Drug
0

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Detailed Information

Few molecules in the complex tapestry of vascular biology are as essential as Angiopoietin-1 (ANGPT1). Key control of blood vessel growth, maturation, and stability, ANGPT1 has been a main focus of study in both developmental biology and therapeutic approaches. Examining ANGPT1's discovery, structure, signaling systems, and possible therapeutic uses, this paper explores its multifarious character.

The Discovery and Structure of ANGPT1

The tale of ANGPT1 started in the late 1990s when scientists worked through the complexity of vascular growth. First found as a ligand for the TIE2 receptor, a tyrosine kinase expressed mostly in endothelial cells, ANGPT1 This finding revealed a signaling mechanism unique from the well-known VEGF route, therefore opening a new avenue of research on vascular biology.

Secreted glycoprotein ANGPT1 is a member of the angiopoietin family and shares ANGPT2, ANGPT3, and ANGPT4. Several important domains define the protein structure of ANGPT1: a coiled-coil domain, an N-terminal super clustering domain, and a C-terminal fibrinogen-like domain. This special arrangement enables ANGPT1 to generate higher-order multimers, a function essential for their biological action.

Receptor binding is driven by the fibrinogen-like domain; oligomerization is mediated by the coiled-coil domain. Crucially, the superclustering domain helps ANGPT1 multimers to develop—necessary for TIE2 activation in endothelial cells. ANGPT1's multimeric character distinguishes it from its antagonistic counterpart, ANGPT2, usually seen as dimers.

Figure 1 illustrates the established and potential signaling pathways activated by Angiopoietin-1 (Ang1) in endothelial cells, highlighting key interactions and regulatory functions of the Tie2 receptor, its relationship with Tie1, and the role of integrins in these signaling processes.Figure 1. Angiopoietin-1 signaling. (Brindle NP, et al., 2006)

Signaling Mechanisms and Cellular Effects

TIE2, a receptor tyrosine kinase expressed mostly in endothelial cells, is the main ANGPT1 receptor. ANGPT1 causes receptor dimerization and autophosphorylation upon binding to TIE2, therefore starting a series of intracellular signaling processes. Recent studies, however, have shown a more complicated signaling terrain showing that ANGPT1 could possibly interact with TIE1 and several integrins, including α5β1.

With the PI3K/AKT pathway being notable, the ANGPT1-TIE2 signaling axis stimulates multiple downstream pathways. Many of ANGPT1's biological effects—including endothelial cell survival, migration, and anti-inflammatory actions— depend on this route. Activating AKT results in phosphorylation and deactivation of the pro-apoptotic protein Bad as well as forkhead transcription factor FOXO1, therefore enhancing cell survival and lowering the expression of genes linked to vascular instability.

By means of various signaling intermediates, ANGPT1 also alters endothelial cell activity. Adaptor proteins include Dok-R and Shc are recruited to phosphorylated TIE2 to control effects on tubule formation and cell migration. Furthermore contributing to its impacts on cell proliferation and survival is ANGPT1's activation of the ERK1/2 MAPK pathway.

ANGPT1's capacity to improve endothelial barrier performance is among the most noticeable cellular impacts. Multiple processes are used to accomplish this: inhibition of inflammatory mediators and regulation of junctional proteins such as VE-cadherin. Strongly stabilizing the vascular endothelium, ANGPT1 has been shown to offset the permeability-inducing effects of inflammatory cytokines and VEGF.

Vascular Stabilization and Maturation

The function of ANGPT1 in vascular biology goes well beyond its effects on cells. In vivo, ANGPT1 is essential for the maturation and stability of recently generated blood vessels. ANGPT1 generated by perivascular cells interacts with endothelial TIE2 during embryonic development to help endothelial cells to be associated with the surrounding matrix and support cells.

Genetic analyses highlight the significance of ANGPT1 in vascular development. Mice missing ANGPT1 or TIE2 die during development from severe vascular abnormalities, defined by a simpler vascular network with less complexity and poor interaction between endothelial cells and the underlying matrix.

ANGPT1 is still very important in the adult vasculature in preserving stability and vascular quiescence. Maintaining the integrity of the endothelium barrier, it counteracts destabilizing elements such ANGPT2 and VEGF. In the framework of pathogenic diseases compromising vascular integrity, including inflammation and ischemia, this stabilizing function is especially crucial.

Anti-inflammatory and Anti-permeability Effects

Strong anti-inflammatory and anti-permeability properties of ANGPT1 biology are among its most exciting features. ANGPT1 has been proven in several experimental models to reduce the expression of pro-inflammatory adhesion molecules including E-selectin, VCAM-1, and ICAM-1 on endothelial cells. Reduced leukocyte adherence and transmigration resulting from this might help to lower vascular inflammation in different pathogenic settings.

Just as significant is ANGPT1's capacity to improve endothelial barrier performance. ANGPT1 preserves vascular integrity by strengthening inter-endothelial junctions and offsetting the permeability-inducing actions of inflammatory mediators and VEGF. This feature has significant consequences for disorders marked by too high vascular leakage, including diabetic retinopathy, sepsis, and acute respiratory distress syndrome.

Therapeutic Potential

The many impacts of ANGPT1 on vascular biology have understandably attracted a lot of attention on their therapeutic value. Direct injection of recombinant protein, gene therapy techniques, and the creation of ANGPT1 mimics have been investigated as many options to maximize the positive impacts of ANGPT1.

Treatment of vascular leakage syndromes is among ANGPT1-based treatments' most exciting uses. ANGPT1's effectiveness in lowering vascular permeability in models of sepsis, acute lung damage, and cerebral ischemia has been shown by preclinical research Furthermore appealing as ANGPT1 may offset the permeability-inducing effects of VEGF is its suitability for treating disorders marked by high VEGF activity, including several eye ailments.

ANGPT1's anti-inflammatory qualities provide yet another therapeutic avenue. ANGPT1 has showed potential in models of transplant arteriosclerosis and diabetic retinopathy in lowering leukocyte intrusion and arterial inflammation. These actions might be helpful in several inflammatory diseases compromising the vasculature.

References:

  1. Brindle NP, Saharinen P, Alitalo K. Signaling and functions of angiopoietin-1 in vascular protection. Circ Res. 2006 Apr 28;98(8):1014-23.
  2. Bafunno V, Firinu D, D'Apolito M, et al. Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema. J Allergy Clin Immunol. 2018 Mar;141(3):1009-1017.
  3. David S, Kümpers P, van Slyke P, et al.  Mending leaky blood vessels: the angiopoietin-Tie2 pathway in sepsis. J Pharmacol Exp Ther. 2013 Apr;345(1):2-6.
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