PAK1
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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
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
Notes
Wikidata Q38779105 . |
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000149269 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030774 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 9697114.
- PMID 9533029.
- ^ S2CID 4332455.
- ^ PMID 7744004.
- ^ PMID 19350548.
- ^ S2CID 5763102.
- S2CID 35272474.
- PMID 24505617.
- ^ )
- ^ "Entrez Gene: PAK1 p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)".
- ^ PMID 23317503.
- PMID 20071173.
- S2CID 7182791.
- PMID 23162743.
- PMID 18420139.
- ^ PMID 23258534.
- PMID 8798379.
- PMID 9774445.
- ^ PMID 10967114.
- PMID 12085993.
- PMID 11356824.
- S2CID 28855687.
- PMID 15066181.
- PMID 21070974.
- ^ PMID 11382770.
- PMID 14585966.
- PMID 17726028.
- PMID 20526801.
- PMID 23885116.
- PMID 10618392.
- PMID 12549928.
- PMID 14583477.
- PMID 14695200.
- PMID 22484303.
- PMID 22493453.
- PMID 22971344.
- PMID 23516476.
- PMID 23811795.
- PMID 25228413.
- PMID 26160174.
- ^ S2CID 36460759.
- PMID 11058583.
- PMID 11719502.
- S2CID 28180002.
- PMID 12151336.
- PMID 12374744.
- PMID 12732616.
- S2CID 12312851.
- S2CID 43600561.
- PMID 14749719.
- ^ PMID 15193260.
- PMID 15378030.
- PMID 15824732.
- PMID 15831477.
- PMID 15833848.
- S2CID 36686511.
- PMID 17389360.
- PMID 17420447.
- PMID 17491012.
- PMID 18283314.
- PMID 18521086.
- PMID 20159552.
- PMID 21822311.
- PMID 22096607.
- PMID 10611223.
- PMID 22105362.
- PMID 12876277.
- PMID 22848689.
- PMID 23260667.
- PMID 25888627.
- PMID 16717130.
- PMID 14530270.
- ^ PMID 15749698.
- S2CID 43415843.
- PMID 23038262.
- PMID 23258534.
- S2CID 23631950.
- PMID 14970201.
- PMID 14749719.
- PMID 11733498.
- ^ S2CID 27574424.
- ^ PMID 9535855.
- PMID 11604394.
- S2CID 25250183.
- PMID 11157752.
- PMID 10026169.
- PMID 8824201.
- PMID 11371639.
- S2CID 4411133.
External links
- PAK1 Info with links in the Cell Migration Gateway Archived 2014-12-11 at the Wayback Machine
- Andrei M (March 23, 2016). "Researchers zoom in on potential treatment for prostate cancer". ZME Science. Retrieved 2016-04-23.