Phosphatase and actin regulator 1 (PHACTR1) is a protein that in humans is encoded by the ''PHACTR1'' gene on

chromosome 6 Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total ...

. It is most significantly expressed in the

globus pallidus The globus pallidus (GP), also known as paleostriatum or dorsal pallidum, is a subcortical structure of the brain. It consists of two adjacent segments, one external, known in rodents simply as the globus pallidus, and one internal, known in rod ...

of the brain. PHACTR1 is an actin and protein phosphatase 1 (PP1) binding protein that binds actin and regulates the reorganization of the actin cytoskeleton. This protein has been associated with

coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...

and

migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

s through genome-wide association studies. The ''PHACTR1'' gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

Structure

Gene

The ''PHACTR1'' gene resides on chromosome 6 at the band 6p24.1 and includes 19

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

s. This gene produces 2 isoforms through

alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...

Protein

PHACTR1 is a member of the

phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...

and actin regulator family and contains 4 RPEL repeats, three of which reside at the C-terminal and bind three actin monomers. 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. PHACTR1 is also predicted to contain 8 PKA

phosphorylation sites In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

and 7 PKC phosphorylation sites found near the RPEL repeats.

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. PHACTR1 can be induced by NRP and VEGF through NRP-1 and VEGF-R1 receptors to control tubulogenesis, actin polymerization, and lamellipodial dynamics. Through this function, PHACTR1 is suggested to play a role in

cell motility Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...

and vascular morphogenesis. Meanwhile, suppression of PHACTR1 increases expression of death cell receptors, leading to extrinsic

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

. 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.

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 A genetic predisposition is a genetic characteristic which influences the possible phenotypic development of an individual organism within a species or population under the influence of environmental conditions. In medicine, genetic susceptibilit ...

to migraines and has a key role in

Marfan Marfan syndrome (MFS) is a multi-systemic genetic disorder that affects the connective tissue. Those with the condition tend to be tall and thin, with long arms, legs, fingers, and toes. They also typically have exceptionally flexible joints ...

and Loeys-Dietz syndromes, two inherited

connective tissue disorders A connective tissue disease (collagenosis) is any disease that has the connective tissues of the body as a target of pathology. Connective tissue is any type of biological tissue with an extensive extracellular matrix that supports, binds togeth ...

causing aortic dissection. In humans, genome-wide association studies have linked PHACTR1 to coronary artery disease. 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.

Clinical marker

Additionally, a multi-locus

genetic risk score In genetics, a polygenic score (PGS), also called a polygenic risk score (PRS), polygenic index (PGI), genetic risk score, or genome-wide score, is a number that summarizes the estimated effect of many genetic variants on an individual's phenotyp ...

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). 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.