Serine/threonine-protein kinase PAK 5 is an enzyme that in humans is encoded by the PAK5 gene. [5] [6] [7]
The PAK5 enzyme is one of three members of Group II PAK family of serine/threonine kinases, [8] [9] and evolutionary conserved across species. [10]
The PAK5 was initially cloned as a brain-specific kinase with a predominant expression in brain with a suggested role in neurite growth in neuronal cells. [8] [9] Selectivity of PAK5 signaling was recognized by its ability to stimulate the JNK kinase but not p38 or ERK kinases. [9]
The PAK5 gene, the longest among the PAK family, contains a total of 12 exons of which four exons are for 5’-UTR and remaining 8 exons for protein coding(Gene from review). Alternative exon splicing of the PAK5 gene generates three transcripts, and one of the transcript encodes a 719 amino acids long protein(Gene from review). The exon splicing of the murine PAK5 gene generates three transcripts, two of which code an identical 719 amino acids long polypeptide while the 2.0-kb transcript is a non-coding RNA with retained intron.
Similar to PAK4, PAK5 consists of a kinase, a CDC42/Rac1 interactive binding (CRIB) motif. [11]
The protein encoded by this gene is a member of the PAK family of Ser/Thr protein kinases. PAK family members are known to be effectors of Rac/Cdc42 GTPases, which have been implicated in the regulation of cytoskeletal dynamics, proliferation, and cell survival signaling. This kinase contains a CDC42/Rac1 interactive binding (CRIB) motif, and has been shown to bind CDC42 in the presence of GTP.
This kinase is predominantly expressed in brain. It is capable of promoting neurite outgrowth, and thus may play a role in neurite development. This kinase is associated with microtubule networks and induces microtubule stabilization. The subcellular localization of this kinase is tightly regulated during cell cycle progression. Alternatively spliced transcript variants encoding the same protein have been described. [7]
Genetic deletion of PAK5 with or without PAK6 deletion in mice has been shown to be associated with a defective locomotion, memory, and learning. [12] [13] PAK5 is co-expressed with DISC1, a psychosis risk gene, and the pathway is likely to be involved in modulating synapse plasticity. [14] Physiological level of PAK5 is linked with an overall physical activity in mice as PAK5 deletion in mice has been shown to be associated with an increased activity upon amphetamine stimulation. [15] PAK5 has been also thought to be one of genetic variants regulating gene expression (eQTL) and its expression associates with an inhibited glucose-regulated secretion of insulin in INS1 cells. [16]
PAK5 expression is positively regulated by Aurora-A and both PAK5 and Aurora-A are co-upregulated in esophageal squamous carcinoma. [17] The levels of PAK5 are regulated by miR-129 in hepatocacinoma cancer cells, [18] and by the binding of the long non-coding RNA Colorectal neoplasia differentially expressed (CRNDE) to miR-186 in glioma cells. [19]
PAK5 phosphorylates Pacsin-1 and Synaptojanin-1 and regulates synaptic vesicle trafficking. [20] PAK5-mediated phosphorylation of GATA1 at S161 and S187 contributes to Epithelial-mesenchymal transition. [21] PAK5 phosphorylation of p120-catenin at S288 plays a role in cytoskeleton remodeling. [22] In addition to the cytoplasm, the PAK5 also localizes in mitochondria and phosphorylates BAD at S112. [23] PAK5 inhibits the MARK2/Par1 activity and modulates microtubules dynamics. [24]
PAK5 levels are upregulated in osteosarcoma, [25] hepatocellular carcinomas, [26] gastric cancer, [27] glioma, [28] esophageal squamous cell cancer, [29] colon cancer, [30] ovarian cancer, [31] and breast cancer. [32] There are also examples of gain-of-function activating PAK5 mutations in non-small-cell lung cancer lung cancer. [33] PAK5 promotes the cell survival and sensitivity of cancer cells to chemotherapy. [17] [31] [34] [35]
 | The 2016 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: Rakesh Kumar, Rahul Sanawar, Xiaodong Li, Feng Li (19 December 2016). "Structure, biochemistry, and biology of PAK kinases". Gene . Gene Wiki Review Series. 605: 20–31. doi:10.1016/J.GENE.2016.12.014. ISSN 0378-1119. PMC 5250584 . PMID 28007610. Wikidata Q38779105. |
p53, also known as Tumor protein P53, cellular tumor antigen p53, or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins are crucial in vertebrates, where they prevent cancer formation. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene.
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.
Cyclin D1 is a protein that in humans is encoded by the CCND1 gene.
Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the RHOA gene. While the effects of RhoA activity are not all well known, it is primarily associated with cytoskeleton regulation, mostly actin stress fibers formation and actomyosin contractility. It acts upon several effectors. Among them, ROCK1 and DIAPH1 are the best described. RhoA, and the other Rho GTPases, are part of a larger family of related proteins known as the Ras superfamily, a family of proteins involved in the regulation and timing of cell division. RhoA is one of the oldest Rho GTPases, with homologues present in the genomes since 1.5 billion years. As a consequence, RhoA is somehow involved in many cellular processes which emerged throughout evolution. RhoA specifically is regarded as a prominent regulatory factor in other functions such as the regulation of cytoskeletal dynamics, transcription, cell cycle progression and cell transformation.
Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene.
DNA-dependent protein kinase, catalytic subunit, also known as DNA-PKcs, is an enzyme that in humans is encoded by the gene designated as PRKDC or XRCC7. DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family. The DNA-Pkcs protein is a serine/threonine protein kinase consisting of a single polypeptide chain of 4,128 amino acids.
Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 (PLK-1) or serine/threonine-protein kinase 13 (STPK13), is an enzyme that in humans is encoded by the PLK1 gene.
Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene.
DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the DDIT3 gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis and has an important role in the cell's stress response.
Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is a signal transduction enzyme that in humans is encoded by the autosomal MAP3K1 gene.
Neural precursor cell expressed developmentally down-regulated protein 9 (NEDD-9) is a protein that in humans is encoded by the NEDD9 gene. NEDD-9 is also known as enhancer of filamentation 1 (EF1), CRK-associated substrate-related protein (CAS-L), and Cas scaffolding protein family member 2 (CASS2). An important paralog of this gene is BCAR1.
Rho guanine nucleotide exchange factor 7 is a protein that in humans is encoded by the ARHGEF7 gene.
Rho guanine nucleotide exchange factor 6 is a protein that, in humans, is encoded by the ARHGEF6 gene.
PAK3 is one of three members of Group I PAK family of evolutionary conserved serine/threonine kinases. PAK3 is preferentially expressed in neuronal cells and involved in synapse formation and plasticity and mental retardation.
Serine/threonine-protein kinase PAK 4 is an enzyme that in humans is encoded by the PAK4 gene.
Growth arrest and DNA-damage-inducible protein GADD45 gamma is a protein that in humans is encoded by the GADD45G gene on chromosome 9. GADD45G is also known as CR6, DDIT2, GRP17, OIG37, and GADD45gamma. GADD45G is involved in several different processes, including sexual development, human-specific brain development, tumor suppression, and the cellular stress response. GADD45G interacts with several other proteins that are involved in DNA repair, cell cycle control, apoptosis, and senescence. Low expression of GADD45G has been associated with many types of cancer.
CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family member p16 and p14arf. Both act as tumor suppressors by regulating the cell cycle. p16 inhibits cyclin dependent kinases 4 and 6 and thereby activates the retinoblastoma (Rb) family of proteins, which block traversal from G1 to S-phase. p14ARF activates the p53 tumor suppressor. Somatic mutations of CDKN2A are common in the majority of human cancers, with estimates that CDKN2A is the second most commonly inactivated gene in cancer after p53. Germline mutations of CDKN2A are associated with familial melanoma, glioblastoma and pancreatic cancer. The CDKN2A gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
Serine/threonine-protein kinase PAK 6 is an enzyme that in humans is encoded by the PAK6 gene.
GTP-binding protein Di-Ras3 (DIRAS3) also known as aplysia ras homology member I (ARHI) is a protein that in humans is encoded by the DIRAS3 gene.
BRAF-activated non-protein coding RNA is a noncoding RNA that in humans is encoded by the BANCR gene. Long non-coding RNAs (lncRNAs) are involved in the intricate network of cancer and contribute significantly to tumorigenesis and progression. BRAF activated non-coding RNA (BANCR), a 693-bp four-exon transcript, was first identified in 2012 as an oncogenic long non-coding RNA in BRAFV600E melanomas cells and was found to be associated with melanoma cell migration. Apart from melanoma, growing evidence has implicated BANCR in the development and progression of a variety of other human malignancies, including retinoblastoma, lung cancer, and gastric cancer, since its discovery. The pattern of expression of BANCR varies according to the kind of cancer, acting as either a tumour suppressor or an accelerator. Functional BANCR may be a useful biomarker for cancer diagnosis and prognosis assessment. BANCR-targeted therapy may also prove to be a promising new treatment option for human cancers.
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