Serine/threonine-protein kinase PAK 2 (PAK2)
The protein contains 524 amino acids for an estimated molecular weight of 58043 Da.
Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell motility, cell cycle progression, apoptosis or proliferation. Acts as downstream effector of the small GTPases CDC42 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Full-length PAK2 stimulates cell survival and cell growth. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Phosphorylates JUN and plays an important role in EGF-induced cell proliferation. Phosphorylates many other substrates including histone H4 to promote assembly of H3.3 and H4 into nucleosomes, BAD, ribosomal protein S6, or MBP. Additionally, associates with ARHGEF7 and GIT1 to perform kinase-independent functions such as spindle orientation control during mitosis. On the other hand, apoptotic stimuli such as DNA damage lead to caspase-mediated cleavage of PAK2, generating PAK-2p34, an active p34 fragment that translocates to the nucleus and promotes cellular apoptosis involving the JNK signaling pathway. Caspase-activated PAK2 phosphorylates MKNK1 and reduces cellular translation. (updated: April 1, 2015)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology.
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Biological Process
Actin cytoskeleton organization
Activation of protein kinase activity
Adherens junction assembly
Apoptotic process
Axon guidance
Bicellular tight junction assembly
Cell migration
Cellular component disassembly involved in execution phase of apoptosis
Cellular response to organic cyclic compound
Dendritic spine development
Fc-epsilon receptor signaling pathway
Innate immune response
Interleukin-12-mediated signaling pathway
Intracellular signal transduction
Mitotic cell cycle
Negative regulation of apoptotic process
Negative regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis
Negative regulation of protein kinase activity
Negative regulation of stress fiber assembly
Peptidyl-serine phosphorylation
Phosphorylation
Positive regulation of extrinsic apoptotic signaling pathway
Positive regulation of peptidyl-tyrosine phosphorylation
Positive regulation of protein tyrosine kinase activity
Protein autophosphorylation
Protein localization to cell-cell junction
Protein phosphorylation
Regulation of apoptotic process
Regulation of axonogenesis
Regulation of cytoskeleton organization
Regulation of defense response to virus by virus
Regulation of growth
Regulation of MAPK cascade
Regulation of mitotic cell cycle
Rho protein signal transduction
Signal transduction
Signal transduction by protein phosphorylation
Stimulatory C-type lectin receptor signaling pathway
Stress-activated protein kinase signaling cascade
T cell costimulation
T cell receptor signaling pathway
Vascular endothelial growth factor receptor signaling pathway
Viral process
Cellular Component
Cell-cell junction
Cytoplasm
Cytosol
Glutamatergic synapse
Nucleoplasm
Nucleus
Perinuclear region of cytoplasm
Plasma membrane
Postsynaptic density
Molecular Function
ATP binding
Cadherin binding
Identical protein binding
Obsolete signal transducer, downstream of receptor, with serine/threonine kinase activity
Protein kinase activity
Protein kinase binding
Protein serine kinase activity
Protein serine/threonine kinase activity
Protein threonine kinase activity
Protein tyrosine kinase activator activity
Rac GTPase binding
Small GTPase binding
The reference OMIM entry for this protein is 605022
P21 protein-activated kinase 2; pak2
P21 cdc42/rac1-activated kinase 1
P21-activated kinase, 65-kd; pak65
DESCRIPTION
Ras (HRAS; 190020)-related GTPases, or p21 proteins, of the Rho (RHOA; 165390) subfamily are critical regulators of signal transduction pathways. The p21-activated kinases (PAKs) are a family of serine/threonine kinases that are central to signal transduction and cellular regulation. PAKs are involved in a variety of cellular processes, including cytoskeletal dynamics, cell motility, gene transcription, death and survival signaling, and cell cycle progression. Consequently, PAKs are implicated in numerous pathologic conditions and in cell transformation. The PAK family is divided into 2 subfamilies, group I and group II, based on domain architecture and regulation. Group I, the conventional PAKs, includes PAK1 (602590), PAK2, and PAK3 (300142), which are activated upon binding the GTP-bound forms of the Rho GTPases CDC42 (116952) and RAC1 (602048). Group II, the nonconventional PAKs, includes PAK4 (605451), PAK5 (PAK7; 608038), and PAK6 (608110), which are active independent of Rho GTPases (reviews by Zhao and Manser (2005) and Eswaran et al. (2008)).CLONING
Using screening assays for GTPases in neutrophil cytosol lysates, followed by peptide sequence analysis and PCR on a placenta cDNA library, Martin et al. (1995) isolated a full-length cDNA encoding human PAK2, which they called PAK65. The deduced PAK2 protein contains RAC (RAC1; 602048)- and CDC42 (116952)-binding domains. PAK2 shares 73% amino acid identity with rat Pak1 (602590), including more than 95% identity within the kinase domain. PAK2 also shares homology with the yeast Ste20 gene. Northern blot analysis revealed that PAK2 is ubiquitously expressed, with highest levels detected in skeletal muscle, ovary, thymus, and spleen. PAK2 transcripts of 7.5, 5, 4.4, and 3 kb were detected in most tissues. The 7.5-kb transcript was predominant in all tissues tested except muscle, where the 7.5- and 3-kb transcripts were equally expressed. In brain, a 3.3-kb transcript was expressed. Genomic Southern blot analysis suggested that the multiple PAK2 mRNAs result from alternative splicing. Western blot analysis using a human PAK2 antibody detected PAK proteins in heart, kidney, liver, and very strongly in purified neutrophil PAK2.GENE FUNCTION
Binding analysis by Martin et al. (1995) confirmed that PAK2 associates with the p21 proteins CDC42 and RAC1, but not with RHOA (ARHA; 165390). Functional analysis determined that CDC42 and RAC1 induce autophosphorylation of PAK2, which stimulates sustained phosphorylation of other substrates. Knaus et al. (1995) biochemically purified PAK1 and PAK2 from neutrophils. They showed that stimulation of neutrophils with the chemoattractant FMLP stimulates kinase activity of PAK1 and PAK2. PAK2 is unique among PAK family members in that it can be activated by proteolytic cleavage to generate a constitutively active fragment, PAK2p34. Activation of PAK2 by RAC or CDC42 stimulates cell survival, whereas caspase-activated PAK2p34 induces a cell death response. Using yeast 2-hybrid analysis, Koeppel et al. (2004) determined that PSGAP (ARHGAP10; 609746) interacted specifically with PAK2p34, but not with active or inactive full-length PAK2, in vitro and in vivo via a region between the GAP and SH3 domains of PSGAP. The interaction with PSGAP inhibited the protein kinase activity of PAK2p34 in vitro and changed the localization of PAK2p24 from the nucleus to the perinuclear region. Furthermore, PSGAP appeared to re ... More on the omim web site
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 605022 was added.
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed