Редактирование: PAK1

Serine/threonine-protein kinase PAK 1 (EC 2.7.11.1) (Alpha-PAK) (p21-activated kinase 1) (PAK-1) (p65-PAK)

==Publications==

{{medline-entry
|title=1,2,3-Triazolyl ester of ketorolac (15K): Boosting both heat-endurance and lifespan of C. elegans by down-regulating [[PAK1]] at nM levels.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29760342
|abstract=[[PAK1]] (RAC/CDC42-activated kinase 1) is the major oncogenic/ageing kinase, and its dysfunction extends the healthy lifespan of C. elegans by activating HSP16 gene. 15K is a highly cell-permeable 1,2,3-triazolyl ester of ketorolac that down-regulates both [[PAK1]] and its down-stream COX-2 in R- and S-forms, respectively. 15K is 500-5,000 times more potent than ketorolac, an old pain-killer, inhibiting the growth of cancer cell lines with IC50 ranging 5-24 nM. Scores of natural and synthetic [[PAK1]]-blockers have been shown to extend the lifespan of small animals such as C. elegans, but none of them has been effective at nM levels. Thus, we examined in vivo effect of 15K at nM levels on the survival rate of C. elegans with or without heat-shock. Like the [[PAK1]]-deficient mutant, 15K (at 50 nM)-treated worm significantly lives longer, is far more heat-resistant and less productive (fertile) than the non-treated counterpart, with an increased expression of HSP16 gene. 15K has been proven to be among the most potent anti-cancerous and longevity-promoting [[PAK1]]-blockers, and therefore has a potential to treat a variety of solid tumours without severe side effect.
|mesh-terms=* Animals
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Down-Regulation
* Gene Expression Regulation, Enzymologic
* Hot Temperature
* Ketorolac
* Longevity
* Molecular Structure
* Triazoles
* p21-Activated Kinases
|keywords=* 1,2,3-triazolyl ester
* C. elegans
* Ketorolac
* PAK1
* anti-cancer
* lifespan
|full-text-url=https://sci-hub.do/10.5582/ddt.2018.01018
}}
{{medline-entry
|title=From bench (laboratory) to bed (hospital/home): How to explore effective natural and synthetic [[PAK1]]-blockers/longevity-promoters for cancer therapy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28814374
|abstract=PAK family kinases are RAC/CDC42-activated kinases that were first found in a soil amoeba 4 decades ago, and 2 decades later, were discovered in mammals as well. Since then at least 6 members of this family have been identified in mammals. One of them called [[PAK1]] has been best studied so far, mainly because it is essential not only for malignant cell growth and metastasis, but also for many other diseases/disorders such as diabetes (type 2), AD (Alzheimer's disease), hypertension, and a variety of inflammatory or infectious diseases, which definitely shorten our lifespan. Moreover, [[PAK1]]-deficient mutant of C. elegans lives longer than the wild-type by 60%, clearly indicating that [[PAK1]] is not only an oncogenic but also ageing kinase. Thus, in theory, both anti-oncogenic and longevity-promoting activities are among the "intrinsic" properties or criteria of "clinically useful" [[PAK1]]-blockers. There are a variety of [[PAK1]]-blocking natural products such as propolis and curcumin which indeed extend the healthy lifespan of small animals such as C. elegans by inducing the autophagy. Recently, we managed to synthesize a series of potent water-soluble and highly cell-permeable triazolyl esters of COOH-bearing [[PAK1]]-blockers such as Ketorolac, [[ARC]] (artepillin C) and CA (caffeic acid) via "Click Chemistry" that boosts their anti-cancer activity over 500-fold, mainly by increasing their cell-permeability, and one of them called 15K indeed extends the lifespan of C. elegans. In this mini-review we shall discuss both synthetic and natural [[PAK1]]-blockers, some of which would be potentially useful for cancer therapy with least side effect (rather promoting the longevity as well).
|mesh-terms=* Animals
* Antineoplastic Agents
* Click Chemistry
* Drug Discovery
* Humans
* Longevity
* Neoplasms
* Protein Kinase Inhibitors
* p21-Activated Kinases
|keywords=* C. elegans
* Cancer
* Click Chemistry
* Longevity
* PAK1
* Propolis
|full-text-url=https://sci-hub.do/10.1016/j.ejmech.2017.07.043
}}
{{medline-entry
|title=Effect of Okinawa Propolis on [[PAK1]] Activity, Caenorhabditis elegans Longevity, Melanogenesis, and Growth of Cancer Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27337169
|abstract=Propolis from different areas has been reported to inhibit oncogenic/aging kinase [[PAK1]], which is responsible for a variety of conditions, including cancer, longevity, and melanogenesis. Here, a crude extract of Okinawa propolis (OP) was tested against [[PAK1]] activity, Caenorhabditis elegans (C. elegans) longevity, melanogenesis, and growth of cancer cells. We found that OP blocks [[PAK1]] and exhibits anticancer activity in the A549 cell (human lung cancer cell) line with IC50 values of 6 μg/mL and 12 μg/mL, respectively. Most interestingly, OP (1 μg/mL) significantly reduces reproduction and prolongs the lifespan of C. elegans by activating the HSP-16.2 gene, as shown in the [[PAK1]]-deficient strain. Furthermore, OP inhibits melanogenesis in a melanoma cell line (B16F10) by downregulating intracellular tyrosinase activity with an IC50 of 30 μg/mL. Our results suggest that OP demonstrated a life span extending effect, C. elegans, anticancer, and antimelanogenic effects via [[PAK1]] inactivation; therefore, this can be a potent natural medicinal supplement against [[PAK1]]-dependent diseases. 
|mesh-terms=* Animals
* Caenorhabditis elegans
* Cell Proliferation
* Humans
* Japan
* Longevity
* Melanins
* Neoplasms
* Propolis
* p21-Activated Kinases
|keywords=* Caenorhabditis elegans
* Okinawa propolis
* PAK1
* cancer
* longevity
* melanogenesis
|full-text-url=https://sci-hub.do/10.1021/acs.jafc.6b01785
}}
{{medline-entry
|title=Several herbal compounds in Okinawa plants directly inhibit the oncogenic/aging kinase [[PAK1]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25639302
|abstract=The p21-activated kinase 1 ([[PAK1]]) is emerging as a promising therapeutic target, and the search for blockers of this oncogenic/aging kinase would be potentially useful for the treatment of various diseases/disorders in the future. Here, we report for the first time the anti-[[PAK1]] activity of compounds derived from three distinct Okinawa plants. 5,6-Dehydrokawain (DK) and dihydro-5,6-dehydrokawain (DDK) from alpinia inhibited directly [[PAK1]] more strongly than mimosine and mimosinol from leucaena. Cucurbitacin I isolated from bitter gourd/melon also exhibited a moderate anti-[[PAK1]] activity. Hispidin, a metabolite of DK, strongly inhibited [[PAK1]] with the IC50 = 5.7 μM. The IC50 of three hispidin derivatives (H1-3) for [[PAK1]] inhibition ranges from 1.2 to 2.0 μM, while mimosine tetrapeptides [mimosine-Phe-Phe-Tyr (MFFY) and mimosine-Phe-Trp-Tyr (MFWY)] inhibit [[PAK1]] at nanomolar level (IC50 of 0.13 and 0.60 μM, respectively). Thus, we hope these derivatives of hispidin and mimosine could be used as potential leading compounds for developing far more potent anti-[[PAK1]] drugs which would be useful for clinical application in the future. 
|mesh-terms=* Aging
* Humans
* Japan
* Neoplasms
* Plants, Medicinal
* Protein Kinase Inhibitors
* p21-Activated Kinases

|full-text-url=https://sci-hub.do/10.5582/ddt.2014.01045
}}
{{medline-entry
|title=Herbal therapeutics that block the oncogenic kinase [[PAK1]]: a practical approach towards [[PAK1]]-dependent diseases and longevity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23943274
|abstract=Over 35 years research on PAKs, RAC/CDC42(p21)-activated kinases, comes of age, and in particular [[PAK1]] has been well known to be responsible for a variety of diseases such as cancer (mainly solid tumors), Alzheimer's disease, acquired immune deficiency syndrome and other viral/bacterial infections, inflammatory diseases (asthma and arthritis), diabetes (type 2), neurofibromatosis, tuberous sclerosis, epilepsy, depression, schizophrenia, learning disability, autism, etc. Although several distinct synthetic [[PAK1]]-blockers have been recently developed, no FDA-approved [[PAK1]] blockers are available on the market as yet. Thus, patients suffering from these [[PAK1]]-dependent diseases have to rely on solely a variety of herbal therapeutics such as propolis and curcumin that block [[PAK1]] without affecting normal cell growth. Furthermore, several recent studies revealed that some of these herbal therapeutics significantly extend the lifespan of nematodes (C. elegans) and fruit flies (Drosophila), and [[PAK1]]-deficient worm lives longer than the wild type. Here, I outline mainly pathological phenotypes of hyper-activated [[PAK1]] and a list of herbal therapeutics that block [[PAK1]], but cause no side (harmful) effect on healthy people or animals.
|mesh-terms=* Animals
* Antineoplastic Agents, Phytogenic
* Communicable Diseases
* Curcumin
* Humans
* Inflammation
* Longevity
* Neoplasms
* Phytotherapy
* Plants, Medicinal
* Propolis
* p21-Activated Kinases
|keywords=* AIDS
* Alzheimer's disease
* King of Bitters
* PAK1
* Thunder god vine
* cancer
* curcumin
* diabetes
* longevity
* neurofibromatosis
* propolis
* tuberous sclerosis
|full-text-url=https://sci-hub.do/10.1002/ptr.5054
}}
{{medline-entry
|title=[[PAK1]]-deficiency/down-regulation reduces brood size, activates HSP16.2 gene and extends lifespan in Caenorhabditis elegans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23524941
|abstract=There is an increasing evidence that the oncogenic kinase [[PAK1]] is responsible not only for malignant transformation, but also for several other diseases such as inflammatory diseases (asthma and arthritis), infectious diseases including malaria, AIDS, and flu, as well as a series of neuronal diseases/disorders (neurofibromatosis, tuberous sclerosis, Alzheimer's diseases, Huntington's disease, epilepsy, depression, learning deficit, etc.) which often cause premature death. Interestingly, a few natural [[PAK1]]-blockers such as curcumin, caffeic acid (CA) and rosmarinic acid (RA) extend the lifespan of the nematode Caenorhabditis elegans or fruit flies. Here, to explore the possibility that C. elegans could provide us with a quick and inexpensive in vivo screening system for a series of more potent but safe (non-toxic) [[PAK1]]-blocking therapeutics, we examined the effects of [[PAK1]]-deficiency or down-regulation on a few selected functions of this worm, including reproduction, expression of HSP16.2 gene, and lifespan. In short, we found that [[PAK1]] promotes reproduction, whereas it inactivates HSP16.2 gene and shortens lifespan, as do PI-3 kinase (AGE-1), TOR, and insulin-like signalling /ILS (Daf-2) in this worm. These findings not only support the "trade-off" theory on reproduction versus lifespan, but also suggest the possibility that the reduced reproduction (or HSP16.2 gene activation) of this worm could be used as the first indicator of extended lifespan for a quick in vivo screening for [[PAK1]]-blockers.
|mesh-terms=* Animals
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Caffeic Acids
* Down-Regulation
* Green Fluorescent Proteins
* Heat-Shock Proteins
* Longevity
* Phenylethyl Alcohol
* Phenylpropionates
* Protein Kinase Inhibitors
* Recombinant Fusion Proteins
* Reproduction
* Signal Transduction
* p21-Activated Kinases

|full-text-url=https://sci-hub.do/10.5582/ddt.2013.v7.1.29
}}