PAK3

PAK3 (p21-activated kinase 2, beta-PAK) is one of three members of Group I PAK family of evolutionary conserved serine/threonine kinases.[5][6][7] PAK3 is preferentially expressed in neuronal cells [8][9] and involved in synapse formation and plasticity and mental retardation.[10][11]

PAK3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1EES
Identifiers
Aliases	PAK3, CDKN1A, MRX30, MRX47, OPHN3, PAK3beta, bPAK, hPAK-3, beta-PAK, ARA, p21 (RAC1) activated kinase 3
External IDs	OMIM: 300142 MGI: 1339656 HomoloGene: 55664 GeneCards: PAK3
Gene location (Human) Chr. X chromosome (human)[1] Band Xq23 Start 110,944,285 bp[1] End 111,227,361 bp[1]
Gene location (Mouse) Chr. X chromosome (mouse)[2] Band X|X F2 Start 143,518,591 bp[2] End 143,797,796 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • transferase activity • nucleotide binding • protein kinase activity • SH3 domain binding • metal ion binding • kinase activity • GO:0001948 protein binding • catalytic activity • GTPase binding • Rho GTPase binding • ATP binding • MAP kinase kinase activity • protein serine/threonine kinase activity • Rac GTPase binding Cellular component • cytoplasm • cytosol • endosome • cell membrane • GO:0097483, GO:0097481 postsynaptic density • glutamatergic synapse Biological process • regulation of neuron projection development • phosphorylation • ephrin receptor signaling pathway • dendrite development • T cell costimulation • synapse organization • cellular response to organic cyclic compound • stimulatory C-type lectin receptor signaling pathway • multicellular organism development • protein phosphorylation • regulation of actin filament polymerization • positive regulation of neuron apoptotic process • dendritic spine development • positive regulation of DNA biosynthetic process • metabolism • T cell receptor signaling pathway • positive regulation of dendritic spine morphogenesis • MAPK cascade • regulation of actin cytoskeleton organization • positive regulation of fibroblast migration • activation of MAPK activity • dendritic spine morphogenesis • Rho protein signal transduction • regulation of mitotic cell cycle • axonogenesis • cell migration • stress-activated protein kinase signaling cascade • regulation of axonogenesis • regulation of apoptotic process • signal transduction by protein phosphorylation • activation of protein kinase activity • regulation of MAPK cascade Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5063	18481
Ensembl	ENSG00000077264	ENSMUSG00000031284
UniProt	O75914	Q61036
RefSeq (mRNA)	NM_001128166 NM_001128167 NM_001128168 NM_001128172 NM_001128173 NM_002578 NM_001324325 NM_001324326 NM_001324327 NM_001324328 NM_001324329 NM_001324330 NM_001324331 NM_001324332 NM_001324333 NM_001324334	NM_001195046 NM_001195047 NM_001195048 NM_001195049 NM_008778
RefSeq (protein)	NP_001121638 NP_001121639 NP_001121640 NP_001121644 NP_001121645 NP_001311254 NP_001311255 NP_001311256 NP_001311257 NP_001311258 NP_001311259 NP_001311260 NP_001311261 NP_001311262 NP_001311263 NP_002569	NP_001181975 NP_001181976 NP_001181977 NP_001181978 NP_032804
Location (UCSC)	Chr X: 110.94 – 111.23 Mb	Chr X: 143.52 – 143.8 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Discovery

PAK3 was initially cloned from a murine fibroblast cDNA library and from a murine embryo cDNA library.[8][9] Like other group I PAKs, PAK3 is stimulated by activated Cdc42 and Rac1.

Gene and spliced variants

The human PAK3 gene, the longest group I family member, is 283-kb long. The PAK3 gene is composed of 22 exons of which 6 exons are for 5’-UTR and generates 13 alternative spliced transcripts. Among PAK3 transcripts, 11 transcripts are for coding proteins ranging from 181- to 580-amino acids long, while remaining two transcripts are non-coding RNAs.[12] The murine PAK3 gene contains 10 transcripts, coding six proteins from 544 amino acids and 559 amino acids long, and four smaller polypeptides from 23 to 366 amino acids.

Protein domains

Similar to PAK1, PAK2 contains a p21-binding domain (PBD) and an auto-inhibitory domain (AID) and exists in an inactive conformation.[13]

Activators and inhibitors

PAK3 activity is stimulated by Dbl, Cdc42 and Cool-2,[14][15] and by AP1 transcription factor.[16] Stimulation of PAK3 activity by upstream stimulators such as Dbl or Cdc42 is inhibited by p50 (Cool-1)[15] PAK3 activity is inhibited by FRAX597, a PAN inhibitor of PAKs.[17]

Functions

PAK3 is overexpressed in neuroendocrine/carcinoids tumors.[18] PAK3 has been shown to be important for synapse formation and plasticity, and contribute to mental retardation.[10] Further, a point mutation in PAK3 gene has been associated with nonsyndromic X-linked mental retardation.[11]

Notes

References

1. GRCh38: Ensembl release 89: ENSG00000077264 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000031284 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Knaus UG, Morris S, Dong HJ, Chernoff J, Bokoch GM (July 1995). "Regulation of human leukocyte p21-activated kinases through G protein--coupled receptors". Science. 269 (5221): 221–3. doi:10.1126/science.7618083. PMID 7618083.
6. Manser E, Chong C, Zhao ZS, Leung T, Michael G, Hall C, Lim L (October 1995). "Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family". The Journal of Biological Chemistry. 270 (42): 25070–8. doi:10.1074/jbc.270.42.25070. PMID 7559638.
7. Kumar A, Molli PR, Pakala SB, Bui Nguyen TM, Rayala SK, Kumar R (July 2009). "PAK thread from amoeba to mammals". Journal of Cellular Biochemistry. 107 (4): 579–85. doi:10.1002/jcb.22159. PMC 2718766. PMID 19350548.
8. Bagrodia S, Taylor SJ, Creasy CL, Chernoff J, Cerione RA (September 1995). "Identification of a mouse p21Cdc42/Rac activated kinase". The Journal of Biological Chemistry. 270 (39): 22731–7. doi:10.1074/jbc.270.39.22731. PMID 7559398.
9. Burbelo PD, Kozak CA, Finegold AA, Hall A, Pirone DM (May 1999). "Cloning, central nervous system expression and chromosomal mapping of the mouse PAK-1 and PAK-3 genes". Gene. 232 (2): 209–15. doi:10.1016/s0378-1119(99)00110-9. PMID 10352232.
10. Boda B, Alberi S, Nikonenko I, Node-Langlois R, Jourdain P, Moosmayer M, Parisi-Jourdain L, Muller D (December 2004). "The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus". The Journal of Neuroscience. 24 (48): 10816–25. doi:10.1523/jneurosci.2931-04.2004. PMC 6730202. PMID 15574732.
11. Allen KM, Gleeson JG, Bagrodia S, Partington MW, MacMillan JC, Cerione RA, Mulley JC, Walsh CA (September 1998). "PAK3 mutation in nonsyndromic X-linked mental retardation". Nature Genetics. 20 (1): 25–30. doi:10.1038/1675. PMID 9731525.
12. Kreis P, Rousseau V, Thévenot E, Combeau G, Barnier JV (August 2008). "The four mammalian splice variants encoded by the p21-activated kinase 3 gene have different biological properties". Journal of Neurochemistry. 106 (3): 1184–97. doi:10.1111/j.1471-4159.2008.05474.x. PMID 18507705.
13. Kumar R, Li DQ (2016). PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology. Advances in Cancer Research. 130. pp. 137–209. doi:10.1016/bs.acr.2016.01.002. ISBN 9780128047897. PMID 27037753.
14. Bagrodia S, Bailey D, Lenard Z, Hart M, Guan JL, Premont RT, Taylor SJ, Cerione RA (August 1999). "A tyrosine-phosphorylated protein that binds to an important regulatory region on the cool family of p21-activated kinase-binding proteins". The Journal of Biological Chemistry. 274 (32): 22393–400. doi:10.1074/jbc.274.32.22393. PMID 10428811.
15. Bagrodia S, Taylor SJ, Jordon KA, Van Aelst L, Cerione RA (September 1998). "A novel regulator of p21-activated kinases". The Journal of Biological Chemistry. 273 (37): 23633–6. doi:10.1074/jbc.273.37.23633. PMID 9726964.
16. Holderness Parker N, Donninger H, Birrer MJ, Leaner VD (2013). "p21-activated kinase 3 (PAK3) is an AP-1 regulated gene contributing to actin organisation and migration of transformed fibroblasts". PLOS ONE. 8 (6): e66892. doi:10.1371/journal.pone.0066892. PMC 3688571. PMID 23818969.
17. Licciulli S, Maksimoska J, Zhou C, Troutman S, Kota S, Liu Q, Duron S, Campbell D, Chernoff J, Field J, Marmorstein R, Kissil JL (October 2013). "FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas". The Journal of Biological Chemistry. 288 (40): 29105–14. doi:10.1074/jbc.m113.510933. PMC 3790009. PMID 23960073.
18. Liu RX, Wang WQ, Ye L, Bi YF, Fang H, Cui B, Zhou WW, Dai M, Zhang J, Li XY, Ning G (August 2010). "p21-activated kinase 3 is overexpressed in thymic neuroendocrine tumors (carcinoids) with ectopic ACTH syndrome and participates in cell migration". Endocrine. 38 (1): 38–47. doi:10.1007/s12020-010-9324-6. PMID 20960100.

External links

• Overview of all the structural information available in the PDB for UniProt: O75914 (Human Serine/threonine-protein kinase PAK 3) at the PDBe-KB.
• Overview of all the structural information available in the PDB for UniProt: Q61036 (Mouse Serine/threonine-protein kinase PAK 3) at the PDBe-KB.