Alternative titles; symbols
HGNC Approved Gene Symbol: ANGPTL6
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38) : 19:10,092,338-10,106,190 (from NCBI)
By searching EST databases for sequences similar to angiopoietins (see ANGPT1, 601667), followed by 5-prime RACE of human fetal RNA, Oike et al. (2003) cloned ANGPTL6, which they called AGF. The deduced 470-amino acid protein has an N-terminal coiled-coil domain and a C-terminal fibrinogen (see 134820)-like domain, both of which are conserved in angiopoietins. Oike et al. (2003) also identified mouse Agf, which encodes a 457-amino acid protein that shares 74% identity with human AGF. Northern blot analysis detected 4.0- and 1.8-kb transcripts expressed abundantly in liver and weakly in heart, brain, lung, kidney, and testis. RT-PCR showed broad expression in hematopoietic cells, with abundant expression in CD41 (see 607759)-positive megakaryocytes/platelets, hematopoietic stem cells, and mast cells. Western blot analysis of mouse tissues detected Agf at an apparent molecular mass of 50 kD predominantly in liver. Immunohistochemical analysis showed Agf expressed in hepatocytes. In situ hybridization and immunohistochemical staining suggested that mast cells secrete Agf.
Romeo et al. (2009) examined levels of ANGPTL4 mRNA in 48 human tissues and found that expression was highest in the liver, with much lower levels in other tissues.
Oike et al. (2003) created transgenic mice overexpressing mouse Agf in epidermal basal keratinocytes and investigated vascularization of their dermal layer. Transgenic mice showed increased numbers of microvessels in their skin and thickened epidermal layer due to enhanced keratinocyte proliferation. These changes led to rapid wound closure. Also in these transgenic mice, Oike et al. (2004) found decreased expression of angiogenic factors other than Agf, suggesting that epidermal AGF directly affects endothelial cells and promotes angiogenesis. In vitro chamber assay revealed that Agf directly promotes chemotactic activity of vascular endothelial cells, and mouse corneal and matrigel plug assays showed that Agf induces neovascularization in vivo. Plasma leakage was observed after direct injection of Agf into the mouse dermis, suggesting that AGF directly induces a permeability change in the local vasculature.
Zheng et al. (2012) showed that the human immune inhibitory receptor leukocyte immunoglobulin-like receptor B2 (LILRB2; 604815) and its mouse ortholog paired immunoglobulin-like receptor (PIRB) are receptors for several angiopoietin-like proteins, including ANGPTL6. LILRB2 and PIRB are expressed on human and mouse hematopoietic stem cells, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of hematopoietic stem cells. In mouse transplantation acute myeloid leukemia models, a deficiency in intracellular signaling of PIRB resulted in increased differentiation of leukemia cells, revealing that PIRB supports leukemia development. Zheng et al. (2012) concluded that their study indicated an unexpected functional significance of classical immune inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development.
Hartz (2005) mapped the ANGPTL6 gene to chromosome 19p13.2 based on an alignment of the ANGPTL6 sequence (GenBank AB054064) with the genomic sequence.
Oike et al. (2005) generated Angptl6 -/- mice, 80% of which died at about embryonic day 13. The surviving null mice developed marked obesity, lipid accumulation in skeletal muscle and liver, and insulin resistance accompanied by reduced energy expenditure relative to controls. Conversely, mice with constitutive overexpression of Agf showed leanness and increased insulin sensitivity resulting from increased energy expenditure, and were also protected from high-fat diet-induced obesity, insulin resistance, and nonadipose tissue steatosis. Hepatic overexpression of Agf by adenoviral transduction in mice fed a high-fat diet resulted in significant weight loss (p less than 0.01) and increased insulin sensitivity. Oike et al. (2005) concluded that AGF is a hepatocyte-derived circulating factor that counteracts obesity and obesity-related insulin resistance.
Hartz, P. A. Personal Communication. Baltimore, Md. 4/26/2005.
Oike, Y., Akao, M., Yasunaga, K., Yamauchi, T., Morisada, T., Ito, Y., Urano, T., Kimura, Y., Kubota, Y., Maekawa, H., Miyamoto, T., Miyata, K., Matsumoto, S., Sakai, J., Nakagata, N., Takeya, M., Koseki, H., Ogawa, Y., Kadowaki, T., Suda, T. Angiopoietin-related growth factor antagonizes obesity and insulin resistance. Nature Med. 11: 400-408, 2005. [PubMed: 15778720] [Full Text: https://doi.org/10.1038/nm1214]
Oike, Y., Ito, Y., Maekawa, H., Morisada, T., Kubota, Y., Akao, M., Urano, T., Yasunaga, K., Suda, T. Angiopoietin-related growth factor (AGF) promotes angiogenesis. Blood 103: 3760-3765, 2004. [PubMed: 14764539] [Full Text: https://doi.org/10.1182/blood-2003-04-1272]
Oike, Y., Yasunaga, K., Ito, Y., Matsumoto, S., Maekawa, H., Morisada, T., Arai, F., Nakagata, N., Takeya, M., Masuho, Y., Suda, T. Angiopoietin-related growth factor (AGF) promotes epidermal proliferation, remodeling, and regeneration. Proc. Nat. Acad. Sci. 100: 9494-9499, 2003. [PubMed: 12871997] [Full Text: https://doi.org/10.1073/pnas.1531901100]
Romeo, S., Yin, W., Kozlitina, J., Pennacchio, L. A., Boerwinkle, E., Hobbs, H. H., Cohen, J. C. Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J. Clin. Invest. 119: 70-79, 2009. [PubMed: 19075393] [Full Text: https://doi.org/10.1172/JCI37118]
Zheng, J., Umikawa, M., Cui, C., Li, J., Chen, X., Zhang, C., Huynh, H., Kang, X., Silvany, R., Wan, X., Ye, J., Canto, A. P., Chen, S.-H., Wang, H.-Y., Ward, E. S., Zhang, C. C. Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 485: 656-660, 2012. Note: Erratum: Nature 488: 684 only, 2012. [PubMed: 22660330] [Full Text: https://doi.org/10.1038/nature11095]