Biology:PHACTR1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Phosphatase and actin regulator 1 (PHACTR1) is a protein that in humans is encoded by the PHACTR1 gene on chromosome 6.[1] It is most significantly expressed in the globus pallidus of the brain.[2] PHACTR1 is an actin and protein phosphatase 1 (PP1) binding protein that binds actin and regulates the reorganization of the actin cytoskeleton.[3] This protein has been associated with coronary artery disease and migraines through genome-wide association studies.[4][5] The PHACTR1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[5]

Structure

Gene

The PHACTR1 gene resides on chromosome 6 at the band 6p24.1 and includes 19 exons.[1] This gene produces 2 isoforms through alternative splicing.[6]

Protein

PHACTR1 is a member of the phosphatase and actin regulator family and contains 4 RPEL repeats, three of which reside at the C-terminal and bind three actin monomers.[6] PHACTR1 binds PP1 in the region containing these RPEL repeats. PHACTR1 wraps around PP1 in a similar way to other PP1 cofactors using a non-canonical RVxF motif, a ϕϕ motif, an Arg motif and a Trp motif. PHACTR1-PP1 complex is an active holophosphatase that binds and dephosphorylates substrates in sequence-denpendent manner.[7]

PHACTR1 is also predicted to contain 8 PKA phosphorylation sites and 7 PKC phosphorylation sites found near the RPEL repeats.[8]

Function

PHACTR1 is a PP1 binding protein, which is reported to be highly expressed in brain and which controls PP1 activity and F-actin remodeling.[9] PHACTR1 can be induced by NRP and VEGF through NRP-1 and VEGF-R1 receptors to control tubulogenesis, actin polymerization, and lamellipodial dynamics.[10] Through this function, PHACTR1 is suggested to play a role in cell motility and vascular morphogenesis.[11] Meanwhile, suppression of PHACTR1 increases expression of death cell receptors, leading to extrinsic apoptosis.[9]

The PHACTR1 locus is commonly identified in multiple genome-wide association studies investigating coronary artery disease and myocardial infarction (MI). However, little is known about the function of PHACTR1 in the heart.[11]

Clinical significance

Upregulation of PHACTR1 by transforming growth factor (TGF)-β has been described in breast cancer cell lines, potentially pointing to a connection with the TGF-β signaling pathway, which is also implicated in genetic predisposition to migraines and has a key role in Marfan and Loeys-Dietz syndromes, two inherited connective tissue disorders causing aortic dissection.[12][13]

In humans, genome-wide association studies have linked PHACTR1 to coronary artery disease.[4] Considering that arterial calcification is a well-known risk factor for coronary artery disease and myocardial infarction, one study tested ∼2.5 million SNPs for an association with coronary artery calcification and aortic calcification in 2620 male individuals who were current or former heavy smokers and underwent chest CT scans in the NELSON trial. No SNPs were associated with aortic calcification on a genome-wide scale. The 9p21 locus was significantly associated with coronary artery calcification (rs1537370). Subsequently, two loci at ADAMTS7 (rs3825807) and at PHACTR1 (rs12526453) showed a nominally significant association with coronary artery calcification and an increased degree of arterial calcification.[4]

Clinical marker

Additionally, a multi-locus genetic risk score study based on a combination of 27 loci, including the PHACTR1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[14]

Another genome-wide association study in 2,326 clinic-based German and Dutch individuals with migraine without aura identified that PHACTR1 (together with ASTN2) as susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.[5][15][16]

In a genome-wide association meta-analysis, PHACTR1 was also identified as a potential key driver of spontaneous coronary artery dissection (SCAD). The study examined data from nearly 2000 SCAD patients and found PHACTR1 and 15 other genes are responsible for subtle genetic changes to SCAD patients blood vessels, increasing the risk of a spontaneous bleed or tear in the wall of the arteries in the heart.[17]

References

  1. ↑ 1.0 1.1 "Entrez Gene: Phosphatase and actin regulator 1". https://www.ncbi.nlm.nih.gov/gene/221692. 
  2. ↑ "BioGPS - your Gene Portal System". http://biogps.org/#goto=genereport&id=221692. 
  3. ↑ "Elucidation of toxicity pathways in lung epithelial cells induced by silicon dioxide nanoparticles". PLOS ONE 8 (9): e72363. 2013-01-01. doi:10.1371/journal.pone.0072363. PMID 24023737. Bibcode: 2013PLoSO...872363O. 
  4. ↑ 4.0 4.1 4.2 "Genome-wide association study of coronary and aortic calcification implicates risk loci for coronary artery disease and myocardial infarction". Atherosclerosis 228 (2): 400–405. June 2013. doi:10.1016/j.atherosclerosis.2013.02.039. PMID 23561647. 
  5. ↑ 5.0 5.1 5.2 "Genome-wide association analysis identifies susceptibility loci for migraine without aura". Nature Genetics 44 (7): 777–782. June 2012. doi:10.1038/ng.2307. PMID 22683712. 
  6. ↑ 6.0 6.1 "PHACTR1 - Phosphatase and actin regulator 1 - Homo sapiens (Human) - PHACTR1 gene & protein". https://www.uniprot.org/uniprot/Q9C0D0. 
  7. ↑ "Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme". eLife 9: e61509. September 2020. doi:10.7554/eLife.61509. PMID 32975518. 
  8. ↑ "Phactrs 1-4: A family of protein phosphatase 1 and actin regulatory proteins". Proceedings of the National Academy of Sciences of the United States of America 101 (18): 7187–7192. May 2004. doi:10.1073/pnas.0401673101. PMID 15107502. Bibcode: 2004PNAS..101.7187A. 
  9. ↑ 9.0 9.1 "Depletion of the novel protein PHACTR-1 from human endothelial cells abolishes tube formation and induces cell death receptor apoptosis". Biochimie 93 (10): 1668–1675. October 2011. doi:10.1016/j.biochi.2011.07.010. PMID 21798305. 
  10. ↑ "Neuropilin-1 regulates a new VEGF-induced gene, Phactr-1, which controls tubulogenesis and modulates lamellipodial dynamics in human endothelial cells". Cellular Signalling 24 (1): 214–223. January 2012. doi:10.1016/j.cellsig.2011.09.003. PMID 21939755. 
  11. ↑ 11.0 11.1 "Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1". Atherosclerosis 250: 95–105. July 2016. doi:10.1016/j.atherosclerosis.2016.04.025. PMID 27187934. 
  12. ↑ "MicroRNA-584 and the protein phosphatase and actin regulator 1 (PHACTR1), a new signaling route through which transforming growth factor-β Mediates the migration and actin dynamics of breast cancer cells". The Journal of Biological Chemistry 288 (17): 11807–11823. April 2013. doi:10.1074/jbc.M112.430934. PMID 23479725. 
  13. ↑ "Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection". Nature Genetics 47 (1): 78–83. January 2015. doi:10.1038/ng.3154. PMID 25420145. 
  14. ↑ "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet 385 (9984): 2264–2271. June 2015. doi:10.1016/S0140-6736(14)61730-X. PMID 25748612. 
  15. ↑ "Replication of migraine GWAS susceptibility loci in Chinese Han population". Headache 54 (4): 709–715. April 2014. doi:10.1111/head.12329. PMID 24666033. 
  16. ↑ "Genome-wide association study reveals three susceptibility loci for common migraine in the general population". Nature Genetics 43 (7): 695–698. June 2011. doi:10.1038/ng.856. PMID 21666692. 
  17. ↑ "Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation". Nature Genetics: 1–9. May 2023. doi:10.1038/s41588-023-01410-1. PMID 37248441. 

Further reading




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