PAK1

Last updated

PAK1
Protein PAK1 PDB 1e0a.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PAK1 , PAKalpha, p21 (RAC1) activated kinase 1, IDDMSSD
External IDs OMIM: 602590; MGI: 1339975; HomoloGene: 1936; GeneCards: PAK1; OMA:PAK1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5058

18479

Ensembl

ENSG00000149269

ENSMUSG00000030774

UniProt

Q13153

O88643

RefSeq (mRNA)

NM_001128620
NM_002576

NM_011035
NM_001357362
NM_001357363
NM_001357364
NM_001357365

RefSeq (protein)

n/a

Location (UCSC) Chr 11: 77.32 – 77.47 Mb Chr 7: 97.44 – 97.56 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene. [5] [6]

PAK1 is one of six members of the PAK family of serine/threonine kinases which are broadly divided into group I (PAK1, PAK2 and PAK3) and group II (PAK4, PAK6 and PAK5/7). [7] [8] The PAKs are evolutionarily conserved. [9] PAK1 localizes in distinct sub-cellular domains in the cytoplasm and nucleus. [10] PAK1 regulates cytoskeleton remodeling, phenotypic signaling and gene expression, and affects a wide variety of cellular processes such as directional motility, invasion, metastasis, growth, cell cycle progression, angiogenesis. [10] [11] PAK1-signaling dependent cellular functions regulate both physiologic and disease processes, including cancer, as PAK1 is widely overexpressed and hyperstimulated in human cancer, at-large. [10] [12] [13]

Discovery

PAK1 was first discovered as an effector of the Rho GTPases in rat brain by Manser and colleagues in 1994. [7] The human PAK1 was identified as a GTP-dependent interacting partner of Rac1 or Cdc42 in the cytosolic fraction from neutrophils, and its complementary DNA was cloned from a human placenta library by Martin and Colleagues in 1995. [8]

Function

PAK proteins are critical effectors that link the Rho family of GTPases (Rho GTPases) to cytoskeleton reorganization and nuclear signaling. PAK proteins, a family of serine/threonine p21-activated kinases, include PAK1, PAK2, PAK3 and PAK4. These proteins serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK1 regulates cell motility and morphology. Alternative transcripts of this gene have been found, but their full-length natures have not been determined. [14]

Stimulation of PAK1 activity is accompanied by a series of cellular processes that are fundamental to living systems. Being a nodular signaling molecule, PAK1 operates to converging station of a large number of signals triggered by proteins on the cell surface as well as upstream activators, and translates into specific phenotypes. At the biochemical level, these activities are regulated by the ability of PAK1 to phosphorylate its effector interacting substrates, which in-turn set-up a cascade of biochemical events cumulating into a cellular phenotypic response. In addition, PAK1 action is also influenced by its scaffolding activity. Examples of PAK1-regulated cellular processes include dynamic of actin and microtubule fibers, critical steps during cell cycle progression, motility and invasion, redox and energy metabolism, cell survival, angiogenesis, DNA-repair, hormone sensitivity, and gene expression. Functional implications of the PAK1 signaling are exemplified by its role in oncogenesis, [9] viral pathogenesis, [15] [16] cardiovascular dysregulation, [17] and neurological disorders. [18]

Gene and spliced variants

The human PAK1 gene is 153-kb long and consists of 23 exons, six exons for 5’-UTR and 17 exons for protein coding (Gene from review). Alternative splicing of six exons generates 20 transcripts from 308-bp to 3.7-kb long; however, only 12 spliced transcripts have open reading frames and are predicted to code ten proteins and two polypeptides. The remaining 8 transcripts range are for non-coding long RNAs from 308-bp to 863-bp long. Unlike the human PAK1, murine PAK1 gene generates five transcripts: three protein-coding from 508-bp to 3.0-kb long, and two transcripts of about 900-bp for non-coding RNAs.

Protein domains

The core domains of the PAK family include a kinase domain in the C-terminal region, a p21-binding domain (PBD), and an auto-inhibitory domain (AID) in group I PAKs. Group I PAKs exist in an inactive, closed homodimer conformation wherein AID of one molecule binds to the kinase domain of another molecule, and activated in both GTPase-dependent and -independent manners. [13]

Activation/inhibition

PAK1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. PAK1 activators relieve this autoinhibition and initiate conformational rearrangements and autophosphorylation events leading to kinase activation.

IPA-3 (1,1′-disulfanediyldinaphthalen-2-ol) is a small molecule allosteric inhibitor of PAK1. Preactivated PAK1 is resistant to IPA-3. Inhibition in live cells supports a critical role for PAK in PDGF-stimulated ERK activation. [19] Reversible covalent binding of IPA-3 to the PAK1 regulatory domain prevents GTPase docking and the subsequent switch to a catalytically active state. [20]

PAK1 knockdown in prostate cancer cells is associated with reduced motility, reduced MMP9 secretion and increased TGFβ expression, which in these cases, is growth inhibitory. However, IPA-3's pharmacokinetic properties as well as undesirable redox effects in cells, due to the continuous reduction of the sulfhydryl moiety, make it unsuitable for clinical development. [20]

Upstream activators

PAK1 activity is stimulated by a large number of upstream activators and signals, ranging from EGF, [21] heregulin-beta 1, [22] VEGF, [23] basic fibroblast growth factor, [24] platelet-derived growth factor, [25] estrogen, [26] lysophosphatidic acid, [27] phosphoinositides, [28] ETK, [29] AKT, [30] JAK2, [31] ERK, [32] casein kinase II, [33] Rac3, [34] chemokine (C-X-C motif) ligand 1, [35] breast cancer anti-estrogen resistance 3, [36] Kaposi's sarcoma-associated herpesvirus-G protein-coupled receptor, [37] hepatitis B virus X protein, [38] STE20-related kinase adaptor protein α, [39] RhoI, [40] Klotho, [41] N-acetylglucosaminyl transferase V, [42] B-Raf proto-oncogene, [43] casein kinase 2-interacting protein 1, [44] and filamin A. [45]

Downstream effector targets

Functions of PAK1 are regulated by its ability to phosphorylate downstream effector substrates, scaffold activity, redistribution to distinct sub-cellular cellular sub-domains, stimulation or repression of expression of its genomic targets either directly or indirectly, or by all of these mechanisms. Representative PAK1 effector substrates in cancer cells include: Stathmin-S16, [46] Merlin-S518, [47] Vimentin-S25-S38-S50-S65-S72, [48] Histone H3-S10, [49] FilaminA-S2152, [45] Estrogen receptor-alpha-S305, [50] signal transducer and activator of transcription 5a-S779, [51] C-terminal binding protein 1-S158, [52] Raf1-S338, [53] Arpc1b-T21, [54] DLC1-S88, [55] phosphoglucomutase 1-T466, [56] SMART/HDAC1-associated repressor protein-S3486-T3568, [57] Tubulin Cofactor B-S65-S128, [58] Snail-S246 [59] vascular endothelial-cadherin-S665, [60] poly(RC) binding protein 1-T60-S246, [61] integrin-linked kinase 1-T173-S246, [62] epithelium-specific Ets transcription factor 1-S207, [63] ErbB3 binding protein 1-T261, [64] nuclear receptor-interacting factor 3-S28, [65] SRC3-delta4-T56-S659-676, [66] beta-catenin-S675, [67] BAD-S111, [68] BAD-S112, S136, [69] MEK1-S298, [70] [71] CRKII-S41, [72] MORC family CW-type zinc finger 2-S739, [73] [74] Paxillin-S258, [15] and Paxillin-S273. [75]

Genomic targets

PAK1 and/or PAK1-dependent signals modulate the expression of its genomic targets, [9] including, vascular endothelial growth factor, [23] Cyclin D1, [76] phosphofructokinase-muscle isoform, [77] nuclear factor of activated T-cell, [77] Cyclin B1, [78] Tissue Factor and tissue factor pathway inhibitor, [79] Metalloproteinase 9, [80] and fibronectin. [81]

Interactions

PAK1 has been shown to interact with:

Notes

Related Research Articles

<span class="mw-page-title-main">PELP-1</span> Mammalian protein found in Homo sapiens

Proline-, glutamic acid- and leucine-rich protein 1 (PELP1) also known as modulator of non-genomic activity of estrogen receptor (MNAR) and transcription factor HMX3 is a protein that in humans is encoded by the PELP1 gene. is a transcriptional corepressor for nuclear receptors such as glucocorticoid receptors and a coactivator for estrogen receptors.

<span class="mw-page-title-main">Integrin-linked kinase</span> Protein-coding gene in the species Homo sapiens

Integrin-linked kinase is an enzyme that in humans is encoded by the ILK gene involved with integrin-mediated signal transduction. Mutations in ILK are associated with cardiomyopathies. It is a 59kDa protein originally identified in a yeast-two hybrid screen with integrin β1 as the bait protein. Since its discovery, ILK has been associated with multiple cellular functions including cell migration, proliferation, and adhesion.

<span class="mw-page-title-main">Transcription factor Jun</span> Mammalian protein found in Homo sapiens

Transcription factor Jun is a protein that in humans is encoded by the JUN gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the JUN gene. c-jun was the first oncogenic transcription factor discovered. The proto-oncogene c-Jun is the cellular homolog of the viral oncoprotein v-jun. The viral homolog v-jun was discovered in avian sarcoma virus 17 and was named for ju-nana, the Japanese word for 17. The human JUN encodes a protein that is highly similar to the viral protein, which interacts directly with specific target DNA sequences to regulate gene expression. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies.

<span class="mw-page-title-main">CDC42</span> Protein-coding gene in the species Homo sapiens

Cell division control protein 42 homolog is a protein that in humans is encoded by the CDC42 gene. Cdc42 is involved in regulation of the cell cycle. It was originally identified in S. cerevisiae (yeast) as a mediator of cell division, and is now known to influence a variety of signaling events and cellular processes in a variety of organisms from yeast to mammals.

<span class="mw-page-title-main">MAPK14</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.

<span class="mw-page-title-main">PTK2</span> Protein-coding gene in humans

PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is encoded by the PTK2 gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes. It has been shown that when FAK was blocked, breast cancer cells became less metastatic due to decreased mobility.

<span class="mw-page-title-main">PAK2</span> Mammalian protein found in Homo sapiens

Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene.

<span class="mw-page-title-main">MAP2K6</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase kinase 6 or MAPK/ERK kinase 6 is an enzyme that in humans is encoded by the MAP2K6 gene, on chromosome 17.

<span class="mw-page-title-main">NCK1</span> Protein-coding gene in the species Homo sapiens

Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.

<span class="mw-page-title-main">RPS6KA1</span> Enzyme

Ribosomal protein S6 kinase alpha-1 is an enzyme that in humans is encoded by the RPS6KA1 gene.

<span class="mw-page-title-main">P70-S6 Kinase 1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">TANK-binding kinase 1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">ARHGEF7</span> Protein-coding gene in humans

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<span class="mw-page-title-main">PAK3</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">BMX (gene)</span> Type of enzyme

Cytoplasmic tyrosine-protein kinase BMX is an enzyme that in humans is encoded by the BMX gene.

<span class="mw-page-title-main">PAK4</span> Mammalian protein found in Homo sapiens

Serine/threonine-protein kinase PAK 4 is an enzyme that in humans is encoded by the PAK4 gene.

<span class="mw-page-title-main">MAP3K2</span> Protein-coding gene in the species Homo sapiens

Mitogen-Activated Protein Kinase Kinase Kinase 2 also known as MEKK2 is an enzyme that in humans is encoded by the MAP3K2 gene.

<span class="mw-page-title-main">MAPK6</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 6 is an enzyme that in humans is encoded by the MAPK6 gene.

<span class="mw-page-title-main">PAK6</span>

Serine/threonine-protein kinase PAK 6 is an enzyme that in humans is encoded by the PAK6 gene.

<span class="mw-page-title-main">Autophosphorylation</span>

Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine or tyrosine residues within protein kinases, normally to regulate the catalytic activity. Autophosphorylation may occur when a kinases' own active site catalyzes the phosphorylation reaction, or when another kinase of the same type provides the active site that carries out the chemistry. The latter often occurs when kinase molecules dimerize. In general, the phosphate groups introduced are gamma phosphates from nucleoside triphosphates, most commonly ATP.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030774 – Ensembl, May 2017
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