Alternative titles; symbols
HGNC Approved Gene Symbol: PAK1
Cytogenetic location: 11q13.5-q14.1 Genomic coordinates (GRCh38): 11:77,322,017-77,530,009 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.5-q14.1 | Intellectual developmental disorder with macrocephaly, seizures, and speech delay | 618158 | Autosomal dominant | 3 |
Ras (HRAS; 190020)-related GTPases, or p21 proteins, of the Rho (RHOA; 165390) subfamily are critical regulators of signal transduction pathways. The p21-activated kinases (PAKs) are a family of serine/threonine kinases that are central to signal transduction and cellular regulation. PAKs are involved in a variety of cellular processes, including cytoskeletal dynamics, cell motility, gene transcription, death and survival signaling, and cell cycle progression. Consequently, PAKs are implicated in numerous pathologic conditions and in cell transformation. The PAK family is divided into 2 subfamilies, group I and group II, based on domain architecture and regulation. Group I, the conventional PAKs, includes PAK1, PAK2 (605022), and PAK3 (300142), which are activated upon binding the GTP-bound forms of the Rho GTPases CDC42 (116952) and RAC1 (602048). Group II, the nonconventional PAKs, includes PAK4 (605451), PAK5 (PAK7; 608038), and PAK6 (608110), which are active independent of Rho GTPases (reviews by Zhao and Manser (2005) and Eswaran et al. (2008)).
By screening rat brain cytosol for proteins that interacted with p21 proteins of the Rho subfamily, Manser et al. (1994) identified 3 proteins that interacted with the GTP-bound forms of human CDC42 and RAC1, but not RHOA. Using PCR, Manser et al. (1994) isolated a rat brain cDNA for 1 of these proteins, Pak1.
Brown et al. (1996) used PCR based on the sequence of rat Pak1 to clone a human PAK1 cDNA from a placenta cDNA library. The human PAK1 gene encodes a 545-amino acid polypeptide that is 98% identical to rat Pak3 and 52% identical to the yeast serine/threonine kinase Ste20.
Knaus et al. (1995) biochemically purified PAK1 and PAK2 from neutrophils.
Knaus et al. (1995) showed that stimulation of neutrophils with the chemoattractant FMLP stimulated the kinase activities of PAK1 and PAK2.
Brown et al. (1996) found that human PAK1 could replace Ste20 in the mating response pathway of yeast. Activity of PAK1 was induced by coexpression with RAC1 or CDC42. PAK1 was thought to act directly on the JNK1 (601158) MAP kinase pathway.
PAK1 protein promotes the disassembly of stress fibers and focal adhesions. Sanders et al. (1999) demonstrated that, in baby hamster kidney-21 and HeLa cells expressing constitutively active PAK1, MLCK (600922) activity and myosin light-chain phosphorylation were decreased, and cell spreading was inhibited. These results indicated that MLCK is a target for PAK1, and that PAKs may regulate cytoskeletal dynamics by decreasing MLCK activity and myosin light-chain phosphorylation.
Parrini et al. (2002) showed that PAK1 forms homodimers in vivo and that its dimerization is regulated by the intracellular level of GTP-CDC42 or GTP-RAC1. The dimerized PAK1 adopts a trans-inhibited conformation: the N-terminal inhibitory portion of one PAK1 molecule in the dimer binds and inhibits the catalytic domain of the other. One GTPase interaction can result in activation of both partners. Another ligand, beta-PIX (605477), can stably associate with dimerized PAK1. Dimerization does not facilitate PAK1 trans-phosphorylation. The authors concluded that the functional significance of dimerization is to allow trans-inhibition.
Vadlamudi et al. (2002) identified filamin A (FLNA; 300017) as a binding partner of PAK1 in a yeast 2-hybrid screen of a mammary gland cDNA library. By mutation analysis, they localized the PAK1-binding region in FLNA to tandem repeat 23 in the C terminus, and the FLNA-binding region in PAK1 between amino acids 52 and 132 in the conserved CDC42 (116952)/RAC (602048)-interacting domain. Endogenous FLNA was phosphorylated by PAK1 on ser2152 following stimulation with physiologic signaling molecules. Following stimulation, FLNA colocalized with PAK1 in membrane ruffles. The ruffle-forming activity of PAK1 was found in FLNA-expressing cells, but not in cells deficient in FLNA.
Using yeast 2-hybrid analysis, Chen et al. (2004) identified PAK1 as a target of OSR1 (OXSR1; 604046). OSR1 phosphorylated thr84 within the N-terminal regulatory domain of PAK1. Replacement of thr84 with gln reduced activation of PAK1 by an active form of CDC42, suggesting that phosphorylation by OSR1 modulates the G protein sensitivity of PAK.
Vaccinia virus, a prototype poxvirus, enters cells in a pH-dependent fashion. Using live cell imaging, Mercer and Helenius (2008) showed that fluorescent virus particles associated with and moved along filopodia to the cell body, where they were internalized after inducing the extrusion of large transient membrane blebs. PAK1 was activated by the virus, and the endocytic process had the general characteristics of macropinocytosis. The induction of blebs, the endocytic event, and infection were all critically dependent on the presence of exposed phosphatidylserine in the viral membrane. Mercer and Helenius (2008) concluded that this phenotype suggested that vaccinia virus uses apoptotic mimicry to enter cells.
Reddy et al. (2008) identified a putative binding site for microRNA-7-1 (MIR7-1; 615239) in the 3-prime UTR of PAK1 mRNA. Chromatin immunoprecipitation and reporter gene analyses confirmed that MIR7-1 bound the PAK1 3-prime UTR and downregulated PAK1 expression. Reddy et al. (2008) found that HOXD10 (142984) upregulated MIR7-1 expression by binding to the MIR7-1 promoter. Overexpression of either HOXD10 or MIR7-1 downregulated PAK1 expression. In MDA-MB231 breast cancer cells, which are highly invasive and tumorigenic, MIR7-1 expression inhibited cell motility, invasiveness, and the ability to grow in an anchorage-independent manner. MIR7-1 also reduced the tumorigenic potential of MDA-MB231 cells in nude mice.
Li et al. (2012) showed that human PAK1 interacted with the zinc finger protein MORC2 (616661). They found that ionizing radiation-induced DNA double-strand breaks were followed by PAK1-dependent phosphorylation of MORC2 on ser739. Phosphorylation of MORC2 activated its DNA- and nucleosome-dependent ATPase activity, causing phosphorylation of histone H2AX (H2AFX; 601772), formation of phosphorylated H2AX foci, chromatin relaxation, and double-strand break repair. Inactivation of PAK1 or MORC2 reduced DNA damage repair. The PAK1-MORC2 pathway was downstream of ATM (607585), but it was independent of the ATM-KAP1 (TRIM28; 601742) DNA damage repair pathway.
Lei et al. (2000) determined the crystal structure of a complex between the N-terminal autoregulatory fragment and the C-terminal kinase domain of PAK1 at 2.3-angstrom resolution. The structure showed that GTPase binding triggers a series of conformational changes, beginning with disruption of a PAK1 dimer and ending with rearrangement of the kinase active site into a catalytically competent state. An inhibitory switch (IS) domain, which overlaps the GTPase-binding region of PAK1, positions a polypeptide segment across the kinase cleft. GTPase binding refolds part of the IS domain and unfolds the rest. The authors noted that a related switch had been seen in the Wiskott-Aldrich syndrome protein (WASP; 301000).
Bekri et al. (1997) mapped the PAK1 gene to 11q13-q14 by inclusion within a mapped clone.
In 2 unrelated boys with intellectual developmental disorder with macrocephaly, seizures, and speech delay (IDDMSSD; 618158), Harms et al. (2018) identified de novo heterozygous missense mutations in the PAK1 gene (Y131C, 602590.0001 and Y429C, 602590.0002). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Patient-derived fibroblasts showed variably increased phosphorylation of certain downstream PAK1 targets, including JNK1 (MAPK8; 601158), AKT1 (164730), and JUN (165160), suggesting a stimulatory effect of mutant PAK1 on these pathways. Patient cells also showed a trend towards increased PAK1 kinase activity compared to controls, consistent with a gain-of-function effect resulting from the mutations. In vitro functional expression assays showed that the mutant proteins had decreased coprecipitation and dimerization with wildtype PAK1 (30-42% compared to controls). In a cell spreading assay, patient fibroblasts showed increased filopodia (spiky morphology) and reduced lamellipodia (ruffles, round) compared to controls, suggesting that the mutations affect actin dynamics and cell morphology. Pharmacologic inhibition of PAK1 activity rescued the cell spreading morphologic abnormalities. The findings indicated a role for PAK1 in brain development.
Huang et al. (2011) noted that knockout of either Pak1 or Pak3 in mice results in no overt abnormality. They found that double knockout (DK) of both Pak1 and Pak3 resulted in mice that were born healthy, with normal brain size and structure. However, postnatal brain growth in DK mice was severely impaired due to reduced neuronal cell volume, reduced axonal and dendritic branching, and reduced synaptic density. Behaviorally, DK mice were hyperactive and anxious, and they exhibited a learning deficit compared with wildtype mice. These structural and functional deficits in DK mice were associated with abnormal electrophysiologic activity in hippocampus and enhanced synaptic cofilin (see 601442) activity.
In a 7-year-old boy (patient 1), born of consanguineous Arabian parents, with intellectual developmental disorder with macrocephaly, seizures, and speech delay (IDDMSSD; 618158), Harms et al. (2018) identified a de novo heterozygous c.392A-G transition (c.392A-G, NM_001128620.1) in the PAK1 gene, resulting in a tyr131-to-cys (Y131C) substitution at a highly conserved residue in the autoinhibitory (AID) domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, ExAC, or gnomAD databases. The patient also carried variants in another gene that were not thought to contribute to the phenotype. Patient fibroblasts showed increased phosphorylation of downstream PAK1 targets, including JNK1 (MAPK8; 601158), AKT1 (164730), and JUN (165160), as well as a trend towards increased PAK1 kinase activity compared to controls, suggesting that the mutation resulted in a gain of function. Harms et al. (2018) hypothesized that the mutation in the AID domain could disrupt dimerization and negatively affect trans-inhibition.
In a 5-year-old boy (patient 2), born of unrelated Caucasian parents, with intellectual developmental disorder with macrocephaly, seizures, and speech delay (IDDMSSD; 618158), Harms et al. (2018) identified a de novo heterozygous c.1286A-G transition (c.1286A-G, NM_001128620.1) in the PAK1 gene, resulting in a tyr429-to-cys (Y429C) substitution at a highly conserved residue in the kinase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, ExAC, or gnomAD databases. The patient also carried variants in other genes that were not thought to contribute to the phenotype. Patient fibroblasts showed increased phosphorylation of downstream PAK1 targets, mainly JUN (165160), as well as a trend towards increased PAK1 kinase activity compared to controls, suggesting that the mutation resulted in a gain of function. Harms et al. (2018) hypothesized that the mutation in the kinase domain might lead to conformational changes that capture the kinase active site into a catalytically competent state.
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