PHACTR1 is a member of thephosphatase and actin regulator family and contains 4 RPEL repeats, three of which reside at theC-terminal and bind three actinmonomers.[10] 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.[11]
PHACTR1 is also predicted to contain 8 PKAphosphorylation sites and 7 PKC phosphorylation sites found near the RPEL repeats.[12]
PHACTR1 is a PP1 binding protein, which is reported to be highly expressed in brain and which controls PP1 activity andF-actin remodeling.[13] PHACTR1 can be induced by NRP andVEGF throughNRP-1 andVEGF-R1 receptors to control tubulogenesis, actinpolymerization, andlamellipodial dynamics.[14] Through this function, PHACTR1 is suggested to play a role incell motility and vascularmorphogenesis.[15] Meanwhile, suppression of PHACTR1 increases expression of death cell receptors, leading to extrinsicapoptosis.[13]
The PHACTR1 locus is commonly identified in multiple genome-wide association studies investigating coronary artery disease andmyocardial infarction (MI). However, little is known about the function of PHACTR1 in theheart.[15]
In humans, genome-wide association studies have linked PHACTR1 to coronary artery disease.[8] 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 atADAMTS7 (rs3825807) and at PHACTR1 (rs12526453) showed a nominally significant association with coronary artery calcification and an increased degree of arterial calcification.[8]
Additionally, a multi-locusgenetic risk score study based on a combination of 27 loci, including thePHACTR1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit fromstatin 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).[18]
Another genome-wide association study in 2,326 clinic-based German and Dutch individuals with migraine without aura identified thatPHACTR1 (together withASTN2) as susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.[9][19][20]
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.[21]
^abJarray R, Allain B, Borriello L, Biard D, Loukaci A, Larghero J, et al. (October 2011). "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.doi:10.1016/j.biochi.2011.07.010.PMID21798305.
^Allain B, Jarray R, Borriello L, Leforban B, Dufour S, Liu WQ, et al. (January 2012). "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.doi:10.1016/j.cellsig.2011.09.003.PMID21939755.
^Fan X, Wang J, Fan W, Chen L, Gui B, Tan G, Zhou J (April 2014). "Replication of migraine GWAS susceptibility loci in Chinese Han population".Headache.54 (4):709–715.doi:10.1111/head.12329.PMID24666033.S2CID205159704.
Lluís-Ganella C, Lucas G, Subirana I, Sentí M, Jimenez-Conde J, Marrugat J, et al. (August 2010). "Additive effect of multiple genetic variants on the risk of coronary artery disease".Revista Espanola de Cardiologia.63 (8):925–933.doi:10.1016/S1885-5857(10)70186-9.PMID20738937.S2CID3879231.
Allain B, Jarray R, Borriello L, Leforban B, Dufour S, Liu WQ, et al. (January 2012). "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.doi:10.1016/j.cellsig.2011.09.003.PMID21939755.
