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ANGPT2

Official Full Name
angiopoietin 2
Organism
Homo sapiens
GeneID
285
Background
This gene belongs to the angiopoietin family of growth factors. The protein encoded by this gene is an antagonist of angiopoietin 1, and both angiopoietin 1 and angiopoietin 2 are ligands for the endothelial TEK receptor tyrosine kinase. Angiopoietin 2 is upregulated in multiple inflammatory diseases and is implicated in the direct control of inflammation-related signaling pathways. The encoded protein affects angiogenesis during embryogenesis and tumorigenesis, disrupts the vascular remodeling ability of angiopoietin 1, and may induce endothelial cell apoptosis. This gene serves a prognostic biomarker for acute respiratory distress syndrome. [provided by RefSeq, Aug 2020]
Synonyms
ANG2; AGPT2; LMPHM10;
Bio Chemical Class
Fibrinogen protein
Protein Sequence
MWQIVFFTLSCDLVLAAAYNNFRKSMDSIGKKQYQVQHGSCSYTFLLPEMDNCRSSSSPYVSNAVQRDAPLEYDDSVQRLQVLENIMENNTQWLMKLENYIQDNMKKEMVEIQQNAVQNQTAVMIEIGTNLLNQTAEQTRKLTDVEAQVLNQTTRLELQLLEHSLSTNKLEKQILDQTSEINKLQDKNSFLEKKVLAMEDKHIIQLQSIKEEKDQLQVLVSKQNSIIEELEKKIVTATVNNSVLQKQQHDLMETVNNLLTMMSTSNSAKDPTVAKEEQISFRDCAEVFKSGHTTNGIYTLTFPNSTEEIKAYCDMEAGGGGWTIIQRREDGSVDFQRTWKEYKVGFGNPSGEYWLGNEFVSQLTNQQRYVLKIHLKDWEGNEAYSLYEHFYLSSEELNYRIHLKGLTGTAGKISSISQPGNDFSTKDGDNDKCICKCSQMLTGGWWFDACGPSNLNGMYYPQRQNTNKFNGIKWYYWKGSGYSLKATTMMIRPADF
Open
Disease
Alzheimer disease, Asthma, Breast cancer, Colorectal cancer, General pain disorder, Ovarian cancer, Renal cell carcinoma, Retinopathy, Sepsis, Sexual dysfunction, Solid tumour/cancer
Approved Drug
1 +
Clinical Trial Drug
13 +
Discontinued Drug
0

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Detailed Information

Within the angiopoietin family, angiopoietin-2 (ANGPT2), also referred to as ANG2, is an essential growth factor. Angiogenesis, vascular remodeling, and inflammation all depend on this protein. ANGPT2 rivals angiopoietin-1 (ANGPT1) for binding to the endothelium TEK receptor tyrosine kinase, often referred to as TIE2. The complex interactions among ANGPT1, ANGPT2, and their common receptor TIE2 coordinate a careful equilibrium in vascular stability and remodeling. Because ANGPT2 is involved in many pathogenic illnesses, including cancer, inflammatory diseases, and ophthalmic problems, it has attracted much interest recently.

Molecular Characteristics and Signaling Pathway

Secreted glycoprotein ANGPT2 is a ligand for the TIE2 receptor. Comprising nine exons, the gene encoding ANGPT2 is found on chromosome 8p23.1 ANGPT2's protein structure consists of a coiled-coil domain at the N-terminus that promotes oligomerization and a fibrinogen-like domain at the C-terminus that binds receptors.

Figure 1 illustrates the Ang-Tie axis.Figure 1. Ang1 and Ang2 contain a super clustering domain, a coiled-coil oligomeric domain, and a fibrinogen-like domain. (Wang R, et al., 2022)

ANGPT2's interaction with the TIE2 receptor drives the main signaling pathway involving it. ANGPT1 is a strong agonist for TIE2, therefore enhancing vascular stability and endothelial cell survival; ANGPT2 is a context-dependent antagonist or mild agonist. ANGPT1 preferentially binds ANGPT2 in the presence of ANGPT1, therefore compromising ANGPT1-induced TIE2 phosphorylation and downstream signaling. Increased vascular permeability and vessel instability follow from this opposing effect.

Fascinatingly, ANGPT2 may cause modest TIE2 phosphorylation in the absence of ANGPT1, suggesting a partial agonistic function. ANGPT2's dual character emphasizes its multifarious role in vascular biology and emphasizes the need for the local microenvironment to define its effects.

Physiological Functions of ANGPT2

Particularly in vascular growth and remodeling, ANGPT2 is very important for many physiological processes. The correct lymphatic system development throughout embryogenesis depends on ANGPT2. Research demonstrating severe lymphatic abnormalities in ANGPT2-deficient mice emphasizes its significance in lymphangiogenesis.

Usually low under normal settings, ANGPT2 expression is quickly raised in response to many stressors like hypoxia, inflammation, or vascular stress in adult tissues. This upregulation triggers vascular remodeling, which lets blood vessels change to fit shifting tissue needs.

ANGPT2's main job is to encourage vascular plasticity. ANGPT2 causes a condition of vascular instability by antagonizing ANGPT1-TIE2 signaling; this is characterized by the loosening of endothelial cell-cell junctions and the separation of pericytes. Angiogenesis requires this instability as it lets endothelial cells react to pro-angiogenic elements such as vascular endothelial growth factor (VEGF).

Within the framework of wound healing, ANGPT2 helps to create new blood vessels required for tissue repair. Early on in the healing process, its expression rises to encourage the sprouting of new capillaries and the modification of existing vessels to satisfy the higher metabolic demand of the mending tissue.

ANGPT2 in Pathological Conditions

Although ANGPT2 is essential for normal physiology, its dysregulation has been linked to many diseases. ANGPT2 is a major factor in disorders marked by abnormal blood vessel development or function as it may cause vascular instability and stimulate angiogenesis.

Cancer and Tumor Angiogenesis

Cancer development and metastases are some of the most well-investigated domains of ANGPT2 involvement. Many studies have shown increased ANGPT2 expression in many forms of cancer, including breast cancer, pancreatic cancer, glioblastoma, gastric cancer, colorectal cancer, hepatocellular carcinoma, and melanoma.

By disrupting current blood vessels and prepping them to react to additional pro-angiogenic elements like VEGF, ANGPT2 drives angiogenesis in the tumor microenvironment. Beyond a certain size, tumor development depends on this mechanism often referred to as the "angiogenic switch." Apart from supplying oxygen and nutrition to the developing tumor, the newly developed blood vessels marked by their aberrant architecture and higher permeability provide possible channels for metastatic dissemination.

Moreover, ANGPT2 has been proven via many channels to encourage tumor cell invasion and metastases. It helps pro-angiogenic and pro-inflammatory cells to be recruited to the tumor site, therefore boosting tumor development and spread. Because poor prognosis in many cancer kinds has been linked to high degrees of ANGPT2 in tumors, anti-cancer treatments find great appeal in this target.

Inflammatory Diseases

ANGPT2 plays a significant role in the pathogenesis of various inflammatory diseases. Its expression is increased in response to inflammatory stimuli and helps explain the vascular alterations seen in disorders like sepsis, acute lung damage, and rheumatoid arthritis.

In sepsis, higher circulating ANGPT2 levels correspond with illness severity and death. ANGPT2 aggravates organ malfunction by encouraging tissue edema and vascular leakage. Analogous to acute lung damage, ANGPT2 helps to boost pulmonary vascular permeability, which causes acute respiratory distress syndrome (ARDS).

ANGPT2 is strongly expressed in the synovial tissue of afflicted joints in rheumatoid arthritis. It aggravates inflammation and synovial angiogenesis, therefore causing joint damage. ANGPT2's interaction with other inflammatory mediators forms a positive feedback loop that sustains the chronic inflammatory state unique to this illness.

Ocular Diseases

Recent studies highlight a critical function for ANGPT2 in many ocular disorders, especially those marked by pathogenic angiogenesis or vascular leakage. Among the disorders including age-related macular degeneration (AMD), diabetic macular edema (DME), and diabetic retinopathy (DR) ANGPT2 has been linked.

Rising levels of ANGPT2 in the vitreous and retina in AMD help to produce aberrant blood vessels in the choroid (choroidal neovascularization). Vision loss and fluid buildup might result from these leaking vessels. In DME and DR, elevated ANGPT2 expression corresponds with disease progression. Retinal vascular permeability and breakdown of the blood-retinal barrier encouraged by ANGPT2 cause macular edema and visual loss.

The discovery of ANGPT2's participation in many ocular illnesses has spurred research on creating medicines aiming at this pathway either by itself or in concert with current anti-VEGF medications.

References:

  1. Huang H, Bhat A, Woodnutt G, Lappe R. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer. 2010 Aug;10(8):575-85.
  2. Khosraviani N, Wu R, Fish JE. Angiopoietin-2: An Emerging Tie to Pathological Vessel Enlargement. Arterioscler Thromb Vasc Biol. 2022 Jan;42(1):3-5.
  3. Mofarrahi M, Hussain SN. Expression and functional roles of angiopoietin-2 in skeletal muscles. PLoS One. 2011;6(7):e22882.
  4. Tsai YC, Lee CS, Chiu YW, et al. Angiopoietin-2, Angiopoietin-1, and subclinical cardiovascular disease in Chronic Kidney Disease. Sci Rep. 2016;6:39400.
  5. Wang R, Yang M, Jiang L, Huang M. Role of Angiopoietin-Tie axis in vascular and lymphatic systems and therapeutic interventions. Pharmacol Res. 2022;182:106331.
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