Serine/threonine-protein kinase PAK 5 is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

that in humans is encoded by the ''PAK5''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. The PAK5 enzyme is one of three members of Group II PAK family of serine/ threonine

kinases In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

, and evolutionary conserved across species.

Discovery

The PAK5 was initially

cloned Cloning is the process of producing individual organisms with identical or virtually identical DNA, either by natural or artificial means. In nature, some organisms produce clones through asexual reproduction. In the field of biotechnology, ...

as a brain-specific kinase with a predominant expression in

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

with a suggested role in

neurite A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in cultur ...

growth in neuronal cells. Selectivity of PAK5 signaling was recognized by its ability to stimulate the JNK kinase but not p38 or ERK kinases.

Gene and spliced variants

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 Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

with retained intron.

Protein domains

Similar to

PAK4 Serine/threonine-protein kinase PAK 4 is an enzyme that in humans is encoded by the ''PAK4'' gene. PAK4 is one of six members of the PAK family of serine/threonine kinases which are divided into group I (PAK1, PAK2 and PAK3) and group II (PAK4, P ...

, PAK5 consists of a kinase, a CDC42/ Rac1 interactive binding (CRIB) motif.

Function

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 The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compo ...

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.

Genetic deletion In genetics, a deletion (also called gene deletion, deficiency, or deletion mutation) (sign: Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA replication. Any number of nucleoti ...

of PAK5 with or without PAK6 deletion in mice has been shown to be associated with a defective

locomotion Locomotion means the act or ability of something to transport or move itself from place to place. Locomotion may refer to: Motion * Motion (physics) * Robot locomotion, of man-made devices By environment * Aquatic locomotion * Flight * Locomo ...

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered ...

, and learning. PAK5 is co-expressed with

DISC1 Disrupted in schizophrenia 1 is a protein that in humans is encoded by the ''DISC1'' gene. In coordination with a wide array of interacting partners, DISC1 has been shown to participate in the regulation of cell proliferation, differentiation, m ...

, a

psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...

risk gene, and the pathway is likely to be involved in modulating synapse plasticity. 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. PAK5 has been also thought to be one of genetic variants regulating gene expression (

eQTL Expression quantitative trait loci (eQTLs) are genomic loci that explain variation in expression levels of mRNAs. Distant and local, trans- and cis-eQTLs, respectively An expression quantitative trait is an amount of an mRNA transcript or a pr ...

) and its expression associates with an inhibited

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

-regulated secretion of insulin in INS1 cells.

Upstream regulators

PAK5 expression is positively regulated by Aurora-A and both PAK5 and Aurora-A are co-upregulated in esophageal squamous carcinoma. The levels of PAK5 are regulated by miR-129 in hepatocacinoma cancer cells, and by the binding of the long non-coding RNA Colorectal neoplasia differentially expressed (CRNDE) to miR-186 in

glioma A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...

cells.

Downstream targets

PAK5 phosphorylates Pacsin-1 and Synaptojanin-1 and regulates synaptic vesicle trafficking. PAK5-mediated phosphorylation of

GATA1 GATA-binding factor 1 or GATA-1 (also termed Erythroid transcription factor) is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by ...

at S161 and S187 contributes to Epithelial-mesenchymal transition. PAK5 phosphorylation of

p120-catenin p120, and called catenin delta-1 is a protein that in humans is encoded by the CTNND1 gene. Function This gene encodes a member of the Armadillo protein family, which function in adhesion between cells and signal transduction. Multiple transl ...

at S288 plays a role in cytoskeleton remodeling. In addition to the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

, the PAK5 also localizes in mitochondria and phosphorylates BAD at S112. PAK5 inhibits the MARK2/Par1 activity and modulates microtubules dynamics.

Clinical significance

PAK5 levels are upregulated in

osteosarcoma An osteosarcoma (OS) or osteogenic sarcoma (OGS) (or simply bone cancer) is a cancerous tumor in a bone. Specifically, it is an aggressive malignant neoplasm that arises from primitive transformed cells of mesenchymal origin (and thus a sarcoma ...

hepatocellular carcinomas Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in t ...

gastric cancer Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymph ...

, esophageal squamous cell cancer, colon cancer,

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...

, and

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...

. There are also examples of gain-of-function activating PAK5 mutations in non-small-cell lung cancer lung cancer. PAK5 promotes the cell survival and sensitivity of cancer cells to

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...

Notes

References

{{PDB Gallery, geneid=57144