PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2)

2011-04-01   Yuan-Hao Hsu 

Department of Chemistry, Biochemistry, Pharmacology, School of Medicine, San Diego, La Jolla, California 92093-0601, USA





Pak2 gene at 193763319 to 193859670 bp from pter contains 96352 bases and 34 exons. Pak2 gene at the alternative location starts at 196466728 and ends at 196559518 bp from pter. The PAK2 gene in this location contains 20 exons.


Atlas Image
The Linear schematic of Pak2. Functional domains, including proline rich regions (P), acidic region (A), p21-binding domain (PBD), Cdc42 and Rac interaction and binding sequence (CRIB) and autoinhibitory domain (AID) are designated. Autophosphorylation sites (*) and caspase 3 cleavage site (v) are marked. The regulatory domain is blue; the protein kinase domain is green; the overlapping region between PBD and AID is pink.


Pak2 has an N-terminal regulatory domain and a C-terminal catalytic domain. In the regulatory domain, Pak2 have several conserved regions, including an autoinhibitory domain (AID), a p21-binding domain (PBD), dimerization domain, proline-rich regions, and an acidic region. The schematic structure of Pak2 is shown in figure above. The catalytic domain of Pak is a conserved bilobal structure in most of the protein kinases.


Pak2 is 58.8 kDa (524 residues) and expressed ubiquitously in mammalian cells.


PAK activation is through disruption of autoinhibition, followed by autophosphorylation. In the inactive state, the AID interacts with the catalytic domain to inhibit its kinase activity. GTP-bound Cdc42 can disrupt autoinhibition, which, in turn, leads to autophosphorylation and activation of PAK. Pak2s basal autophosphorylation activity is observed and Pak2 is autophosphorylated at 5 sites, serines 19, 20, 55, 192 and 197. Additional three phosphorylation sites (serines 141 and 165 and threonine 402) are autophosphorylated in the presence of Cdc42(GTP) and ATP. Autophosphorylation of Thr402 in the activation loop is required for the kinase activity of Pak2.
Pak2 can be activated in response to a lot of stresses. Moderate stresses, like hyperosmolarity, ionizing radiation, DNA-damaging agents and serum-deprivation, induce Pak2 activation in cells and lead to cell cycle arrest at G2/M. Activated Pak2 inhibits translation by phosphorylation of various substrates. Pak2 has specific protein substrates, e.g. histone 4, myosin light chain (MLC), prolactin, c-Abl, eukaryote translation initiation factor 3 (eIF3), eIF4B, eIF4G, and Mnk1. Pak2 recognizes the consensus sequence (K/RRXS).
Pak2 is the only member of the PAK family that is directly activated by caspase 3. When Pak2 is cleaved and activated by caspase 3, Pak2 promotes the morphological and biochemical changes of apoptosis. The pro-apoptosis protease, caspase 3 cleaves Pak2 after Asp 212, and thus produces a p27 fragment containing primarily the regulatory domain, and a p34 fragment containing a small piece of the regulatory domain and the entire catalytic domain. Autophosphorylation results in a constitutively active p34 kinase domain. The nuclear import signal (245-251) is required for nuclear localization. Disruption of the region (197-246), containing nuclear export signal results in the nuclear localization of the Pak2 p34 fragment.


Pak1, Pak2 and Pak3 are highly homologous. The primary sequence of human Pak2 is 72 % identical to Pak1 and 71 % identical to Pak3.



None is reported.

Implicated in

Entity name
Huang (2004) showed Pak2 is a negative regulator of Myc and suggested Pak2 may be the product of a tumor suppressor gene. Coniglio (2008) reported Pak2 mediates tumor invasion in breast carcinoma cells. Inhibition of RhoA in Pak2-depleted cells decreases MLC phosphorylation and restores cell invasion. Also, the NF2 tumor suppressor Merlin is a substrate of Pak2. Wilkes (2009) showed that Erbin regulates the function of Merlin through Pak2 binding to Merlin.
Entity name
Human immunodeficiency virus type 1 HIV-1.
Human immunodeficiency virus type 1 Nef associates with a active Pak2 independently of binding to Nck or PIX. Nef recruits the GEF Vav1 to plasma membrane to associate with Pak2.


Pubmed IDLast YearTitleAuthors
184113042008Pak1 and Pak2 mediate tumor cell invasion through distinct signaling mechanisms.Coniglio SJ et al
97744401998Differential effects of PAK1-activating mutations reveal activity-dependent and -independent effects on cytoskeletal regulation.Frost JA et al
100757011999Multisite autophosphorylation of p21-activated protein kinase gamma-PAK as a function of activation.Gatti A et al
189845902008Analysis of conformational changes during activation of protein kinase Pak2 by amide hydrogen/deuterium exchange.Hsu YH et al
202091592010Reciprocally coupled residues crucial for protein kinase Pak2 activity calculated by statistical coupling analysis.Hsu YH et al
147493742004Negative control of the Myc protein by the stress-responsive kinase Pak2.Huang Z et al
128534462003Caspase-activated PAK-2 is regulated by subcellular targeting and proteasomal degradation.Jakobi R et al
117824912002Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization.Kissil JL et al
93910791997Activation of hPAK65 by caspase cleavage induces some of the morphological and biochemical changes of apoptosis.Lee N et al
162810552005Inhibition of cap-dependent translation via phosphorylation of eIF4G by protein kinase Pak2.Ling J et al
81077741994A brain serine/threonine protein kinase activated by Cdc42 and Rac1.Manser E et al
152349642004Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk.Orton KC et al
113458982001Cytostatic p21 G protein-activated protein kinase gamma-PAK.Roig J et al
91710631997Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2.Rudel T et al
98585841999Genetic evidence for Pak1 autoinhibition and its release by Cdc42.Tu H et al
94050391997Determinants for substrate phosphorylation by p21-activated protein kinase (gamma-PAK).Tuazon PT et al
97868691998Cleavage and activation of p21-activated protein kinase gamma-PAK by CPP32 (caspase 3). Effects of autophosphorylation on activity.Walter BN et al
192890882009Erbin and the NF2 tumor suppressor Merlin cooperatively regulate cell-type-specific activation of PAK2 by TGF-beta.Wilkes MC et al
95287871998A conserved negative regulatory region in alphaPAK: inhibition of PAK kinases reveals their morphological roles downstream of Cdc42 and Rac1.Zhao ZS et al

Other Information

Locus ID:

NCBI: 5062
MIM: 605022
HGNC: 8591
Ensembl: ENSG00000180370


dbSNP: 5062
ClinVar: 5062
TCGA: ENSG00000180370


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
ErbB signaling pathwayKEGGko04012
Axon guidanceKEGGko04360
Focal adhesionKEGGko04510
T cell receptor signaling pathwayKEGGko04660
Regulation of actin cytoskeletonKEGGko04810
Renal cell carcinomaKEGGko05211
MAPK signaling pathwayKEGGhsa04010
ErbB signaling pathwayKEGGhsa04012
Axon guidanceKEGGhsa04360
Focal adhesionKEGGhsa04510
T cell receptor signaling pathwayKEGGhsa04660
Regulation of actin cytoskeletonKEGGhsa04810
Renal cell carcinomaKEGGhsa05211
Ras signaling pathwayKEGGhsa04014
Infectious diseaseREACTOMER-HSA-5663205
HIV InfectionREACTOMER-HSA-162906
Host Interactions of HIV factorsREACTOMER-HSA-162909
The role of Nef in HIV-1 replication and disease pathogenesisREACTOMER-HSA-164952
Nef and signal transductionREACTOMER-HSA-164944
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
TCR signalingREACTOMER-HSA-202403
Generation of second messenger moleculesREACTOMER-HSA-202433
Costimulation by the CD28 familyREACTOMER-HSA-388841
CD28 co-stimulationREACTOMER-HSA-389356
CD28 dependent Vav1 pathwayREACTOMER-HSA-389359
Innate Immune SystemREACTOMER-HSA-168249
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
C-type lectin receptors (CLRs)REACTOMER-HSA-5621481
CD209 (DC-SIGN) signalingREACTOMER-HSA-5621575
Signal TransductionREACTOMER-HSA-162582
Signaling by VEGFREACTOMER-HSA-194138
VEGFR2 mediated vascular permeabilityREACTOMER-HSA-5218920
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK6/MAPK4 signalingREACTOMER-HSA-5687128
Signaling by Rho GTPasesREACTOMER-HSA-194315
RHO GTPase EffectorsREACTOMER-HSA-195258
RHO GTPases activate PAKsREACTOMER-HSA-5627123
Programmed Cell DeathREACTOMER-HSA-5357801
Apoptotic execution phaseREACTOMER-HSA-75153
Stimulation of the cell death response by PAK-2p34REACTOMER-HSA-211736
Regulation of ApoptosisREACTOMER-HSA-169911
Regulation of activated PAK-2p34 by proteasome mediated degradationREACTOMER-HSA-211733
Regulation of PAK-2p34 activity by PS-GAP/RHG10REACTOMER-HSA-211728
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Semaphorin interactionsREACTOMER-HSA-373755
Sema3A PAK dependent Axon repulsionREACTOMER-HSA-399954
Signaling by Robo receptorREACTOMER-HSA-376176
Activation of RacREACTOMER-HSA-428540
EPH-Ephrin signalingREACTOMER-HSA-2682334
Ephrin signalingREACTOMER-HSA-3928664

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
183193012008Cdc42- and Rac1-mediated endothelial lumen formation requires Pak2, Pak4 and Par3, and PKC-dependent signaling.92
206914062010Microdeletions of 3q29 confer high risk for schizophrenia.91
184113042008Pak1 and Pak2 mediate tumor cell invasion through distinct signaling mechanisms.60
159084322005Binding of activated alpha2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK.58
124538772002Cdc42/Rac1-dependent activation of the p21-activated kinase (PAK) regulates human platelet lamellipodia spreading: implication of the cortical-actin binding protein cortactin.46
150478252004Human immunodeficiency virus type 1 Nef activates p21-activated kinase via recruitment into lipid rafts.42
166171112006Posttranslational myristoylation of caspase-activated p21-activated protein kinase 2 (PAK2) potentiates late apoptotic events.33
168679952006Transforming growth factor beta activation of c-Abl is independent of receptor internalization and regulated by phosphatidylinositol 3-kinase and PAK2 in mesenchymal cultures.32
183449742008Clathrin-independent endocytosis used by the IL-2 receptor is regulated by Rac1, Pak1 and Pak2.30
162810552005Inhibition of cap-dependent translation via phosphorylation of eIF4G by protein kinase Pak2.29


Yuan-Hao Hsu

PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2)

Atlas Genet Cytogenet Oncol Haematol. 2011-04-01

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