PAK5

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Serine / threonine protein kinase PAK 5
Serine / threonine protein kinase PAK 5
Ribbon model of the serine / threonine protein kinase PAK 5 according to PDB  2F57
other names
  • p21 protein (Cdc42 / Rac) -activated kinase 5
  • p21 (CDKN1A) -activated kinase 5
  • p21 activated kinase 5

Existing structural data : 2BVA , 2C30 , 2CDZ

Properties of human protein
Mass / length primary structure 80,745 daltons / 719 amino acids (isoform 1)

70,152 daltons / 632 amino acids (isoform 2)

Isoforms 2
Identifier
Gene names PAK5 KIAA1264, PAK7
External IDs
Enzyme classification
EC, category 2.7.11.1
Occurrence
Homology family CLU_000288_26_6
Orthologue
human House mouse
Entrez 57144 241656
Ensemble ENSG00000101349 ENSMUSG00000039913
UniProt Q9P286 Q8C015
Refseq (mRNA) NM_020341 NM_172858
Refseq (protein) NP_065074 NP_766446
Gene locus Chr 20: 9.54 - 9.84 Mb Chr 2: 136.08 - 136.39 Mb
PubMed search 57144 241656

Serine / threonine protein kinase PAK 5 is an enzyme that is encoded by the PAK5 gene , also called PAK7 , and belongs to the p21-activated kinases . PAK5 is mainly expressed in the brain and plays a role in the formation of pseudopods in the growth cone and in the sprouting of processes of developing neurons ( neurites ).

Since the enzyme is also an important role in cell regulation, apoptosis , cell proliferation , migration plays and invasion, it can at a dysregulation of PAK5 for ovarian cancer , cervical cancer , malignant melanoma , osteosarcoma , renal cancer , breast cancer , gastric cancer , colon cancer cause, etc..

It should be noted that PAK5 can certainly bind to CDC42 and RAC1, but that this has no influence on the kinase activity of PAK5.

Gene structure

The PAK5 gene is encoded in the human organism by twelve exons that are located on chromosome band 20p12. A CpG island of approximately 1  kb is located in a higher region of the PAK 5 gene locus (approximately 6.05-6.051 Mb).

function

The serine / threonine protein kinase PAK 5 participates in many cellular processes, such as cytoskeletal regulation , cell migration , cell proliferation and suppression of cell death and thus regulates cell survival. It is therefore understandable that overexpression of PAK5 can be found in numerous tumors and could therefore function as a possible signal molecule in the cellular signal transduction of tumor growth.

Activation by various effectors, including EGF receptors, results in a conformational change and a subsequent autophosphorylation of several serine and / or threonine residues . It also phosphorylates the proto-oncogene RAF1 (and thus activates it) and stimulates its kinase activity. In the cell, PAK5 forms a solid complex with RAF1. In addition, PAK5 is able to get a subgroup of RAF1 to the mitochondria and thus influence the RAF1-dependent signal transmission at the mitochondrion.

Furthermore, cell survival is promoted by phosphorylation of the proapoptotic protein Bcl-2 antagonist-of-cell-death (BAD) on serine-112, as this prevents BAD from reaching the mitochondria and thus stops the caspase cascade, which otherwise leads to apoptosis.

It may phosphorylate the protein CTNND1 to enable regulation of the cytoskeleton and cell morphology. The p21-activated kinase PAK5 is more strongly expressed in the brain than in other areas of the body. It can promote the outgrowth of neurons and thus plays a role in neuronal development. Especially in mice, PAK5 (and PAK6) is important for learning and memory. It is mostly located in the nucleus and mitochondrion , but also in the cytoplasm. Above all, the mitochondrial localization is essential for the survival of the cell.

Interaction with other proteins

PAK5 has a domain (CRIB motif) at the N terminus with which it can interactively bind to CDC42 / Rac1 and a Ste20-like kinase domain at the C terminus. PAK5 binds preferentially to CDC42 (in the presence of GTP) and thus the CRIB motif makes this interaction possible. However, this interaction does not result in any kinase activity (i.e. activation), which would be the case with PAK1, PAK2 and PAK3. Overexpression of PAK5 activates the JNK pathway. The enzyme is also associated with the microtubule network , in which it can induce stability through enzyme inhibition of MARK2 , but also instability in the F-actin network , which causes stress fibers and focal adhesion to disappear, allowing filopodia to develop. The localization of the kinase is therefore strictly regulated, especially during the cell cycle. It also interacts with RHOD to reach other cell compartments that it would not have reached just by interacting with CDC42. PAK5 also interacts with RHOH .

Animal model

The CHO cells of the Chinese dwarf hamster ( Cricetulus griseus ) contain the protein kinases PAK5 and MARK2, which are located in the vesicles and sometimes also in the endosomes , which contain the transcription factors AP-1 and AP-2 . By in situ hybridization can be detected strong expression of PAK5 in mouse brains, especially in the cerebellum , the cerebral cortex and olfactory bulb . Particularly in the cerebellum, intense expression in the granular layer ( stratum granulosum ) can be detected, as well as moderate expression in the molecular layer ( stratum molecularulare ) of the Purkinje cells .

Individual evidence

  1. ↑ a b S. Cotteret, ZM Jaffer, A. Beeser, J. Chernoff: p21-Activated Kinase 5 (Pak5) Localizes to Mitochondria and Inhibits Apoptosis by Phosphorylating BAD. In: Molecular and Cellular Biology. 23, 2003, p. 5526, doi : 10.1128 / mcb.23.16.5526-5539.2003 .
  2. ↑ Akhilesh Pandey, Ippeita Dan: Cloning and characterization of PAK5, a novel member of mammalianp21-activated kinase-II subfamily that is predominantly expressed in brain . In: Oncogene . 21, No. 8, May 30, 2002, pp. 3939-3948. doi : 10.1038 / sj.onc.1205478 . PMID 12032833 .
  3. ↑ Yi-Yang Wen, Jun-Nian Zheng, Dong-Sheng Pei: An oncogenic kinase: putting PAK5 forward. In: Expert Opinion on Therapeutic Targets. 18, 2014, p. 807, doi : 10.1517 / 14728222.2014.918103 .
  4. ↑ Xiaochong Wu, Heather S. Carr, Ippeita Dan, Peter P. Ruvolo, Jeffrey A. Frost: p21 activated kinase 5 activates Raf-1 and targets it to mitochondria. In: Journal of Cellular Biochemistry. 105, 2008, p. 167, doi : 10.1002 / jcb.21809 .
  5. ↑ a b UniProt Q9P286
  6. ↑ a b PAK5 p21 (RAC1) activated kinase 5 (Homo sapiens, human)
  7. ↑ Audrey Minden: PAK 4-6 in cancer and neuronal development. In: Cellular Logistics. 2, 2014, p. 95, doi : 10.4161 / cl.21171 .
  8. ↑ PAK5. In: GeneCards (English).
  9. ↑ Akhilesh Pandey, Ippeita Dan, Troels Z Kristiansen, Norinobu M Watanabe, Jesper Voldby, Eriko Kajikawa, Roya Khosravi-Far, Blagoy Blagoev, Matthias Mann: Cloning and characterization of PAK5, a novel member of mammalianp21-activated kinase-II subfamily that is predominantly expressed in the brain. In: Oncogene. 21, 2002, p. 3939, doi : 10.1038 / sj.onc.1205478 .
  10. ↑ Dorthe Matenia, Bettina Griesshaber, Xiao-yu Li, Anja Thiessen, Cindy Johne, Jian Jiao, Eckhard Mandelkow, Eva-Maria Mandelkow: PAK5 Kinase Is an Inhibitor of MARK / Par-1, Which Leads to Stable Microtubules and Dynamic Actin. In: Molecular Biology of the Cell. 16, 2005, p. 4410, doi : 10.1091 / mbc.E05-01-0081 .
  11. ↑ Xiaochong Wu, Jeffrey A. Frost: Multiple Rho proteins regulate the subcellular targeting of PAK5. In: Biochemical and Biophysical Research Communications. 351, 2006, p. 328, doi : 10.1016 / j.bbrc.2006.09.172 .
  12. ↑ Dorthe Matenia, Bettina Griesshaber: PAK5 Kinase Is an Inhibitor of MARK / Par-1, Which Leads to Stable Microtubules and Dynamic Actin . In: Molecular Biology of the Cell (MBoC) . June 29, 2005.
  13. ↑ PAK5.  In: Online Mendelian Inheritance in Man . (English)