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protein metals Protein-protein interface(s) links
Transferase PDB id
1f3m
Jmol
Contents
Protein chains
70 a.a. *
287 a.a. *
Metals
IOD ×28
Waters ×582
* Residue conservation analysis
PDB id:
1f3m
Name: Transferase
Title: Crystal structure of human serine/threonine kinase pak1
Structure: Serine/threonine-protein kinase pak-alpha. Chain: a, b. Fragment: pak1 autoregulatory domain (70-149). Engineered: yes. Serine/threonine-protein kinase pak-alpha. Chain: c, d. Fragment: kinase domain (249-545). Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
Resolution:
2.30Å     R-factor:   0.237     R-free:   0.258
Authors: M.Lei,W.Lu,W.Meng,M-C.Parrini,M.J.Eck,B.J.Mayer,S.C.Harrison
Key ref:
M.Lei et al. (2000). Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch. Cell, 102, 387-397. PubMed id: 10975528 DOI: 10.1016/S0092-8674(00)00043-X
Date:
05-Jun-00     Release date:   29-Jun-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q13153  (PAK1_HUMAN) -  Serine/threonine-protein kinase PAK 1
Seq:
Struc: 		 
Seq:
Struc: 		545 a.a.
70 a.a.
Protein chains
Pfam   ArchSchema ?
Q13153  (PAK1_HUMAN) -  Serine/threonine-protein kinase PAK 1
Seq:
Struc: 		 
Seq:
Struc: 		545 a.a.
287 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, C, B, D: E.C.2.7.11.1  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
 + protein
 = ADP
 + phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein amino acid phosphorylation   1 term 
  Biochemical function     protein kinase activity     3 terms  

 

 
    reference    
 
 
DOI no: 10.1016/S0092-8674(00)00043-X Cell 102:387-397 (2000)
PubMed id: 10975528  
 
 
Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch.
M.Lei, W.Lu, W.Meng, M.C.Parrini, M.J.Eck, B.J.Mayer, S.C.Harrison.
 
  ABSTRACT  
 
The p21-activated kinases (PAKs), stimulated by binding with GTP-liganded forms of Cdc42 or Rac, modulate cytoskeletal actin assembly and activate MAP-kinase pathways. The 2.3 A resolution crystal structure of a complex between the N-terminal autoregulatory fragment and the C-terminal kinase domain of PAK1 shows that GTPase binding will trigger a series of conformational changes, beginning with disruption of a PAK1 dimer and ending with rearrangement of the kinase active site into a catalytically competent state. An inhibitory switch (IS) domain, which overlaps the GTPase binding region of PAK1, positions a polypeptide segment across the kinase cleft. GTPase binding will refold part of the IS domain and unfold the rest. A related switch has been seen in the Wiskott-Aldrich syndrome protein (WASP).
 
  Selected figure(s)  
 
Figure 4.
Figure 4. The Inhibited Conformation of PAK1 Kinase Domain(A) The inhibited active site of PAK1. The view is from the right of the C chain in Figure 2A. The KI segment of the autoregulatory fragment occupies the cleft between the N lobe and the C lobe of the kinase domain. Lys141 makes hydrogen bonds with Asp389 of the catalytic loop and Asp407 of the activation loop. Asp389 is the catalytic base in an active kinase. The activation loop is forced to make a turn (407–413), which blocks the contact between Glu315 of Helix C and K299R and prevents binding of ATP. The arrow indicates the shift in helix C that would be required for it to move to its expected position in an active enzyme.(B) Hydrophobic contacts from helix A and strands 4 and 5 stabilize helix C in the inhibited conformation. The inner sides of helices A and C and strands 4 and 5 form a highly hydrophobic core. We expect that without helix A the small lobe of the kinase domain would not be stable. 		Figure 6.
Figure 6. Model for PAK1 Activation(A) In the autoinhibited conformation, PAK1 is an asymmetric dimer. The inhibitory switch (IS) domain associates tightly with the C lobe of the kinase domain. The kinase inhibitory (KI) segment (137–149) occupies the cleft of the kinase domain and stabilizes a disabled catalytic site. The color scheme for PAK1 matches that in Figure 1. Numerals indicate residue numbers. The connections between residues 147 and 249 in the two partners are not shown, because we do not yet know whether the links are made in cis or in trans.(B) Binding of GTP-loaded Cdc42 (or Rac) with the PAK1 p21 binding domain (PBD) disrupts the dimer and unfolds the IS domain (symbolized by its reversion to a formless oval). The conformational change withdraws the KI segment from the cleft of the kinase domain and releases the activation loop. Phosphorylation of Thr423 (PT423) will activate the enzyme.(C) Once Thr423 has been phosphorylated, PAK can autophosphorylate at several sites (phosphoserine: PS) within the first 250 amino acids. These modifications prevent the kinase from reverting to an inactive conformation.
 
  The above figures are reprinted by permission from Cell Press: Cell (2000, 102, 387-397) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21170023 A.S.Selyunin, S.E.Sutton, B.A.Weigele, L.E.Reddick, R.C.Orchard, S.M.Bresson, D.R.Tomchick, and N.M.Alto (2011).
The assembly of a GTPase-kinase signalling complex by a bacterial catalytic scaffold.
  Nature, 469, 107-111.
PDB codes: 3pcr 3pcs
20453877 A.Watari, N.Iwabe, H.Masuda, and M.Okada (2010).
Functional transition of Pak proto-oncogene during early evolution of metazoans.
  Oncogene, 29, 3815-3826.  
19937092 D.Guo, J.J.Zhang, and X.Y.Huang (2010).
A new Rac/PAK/GC/cGMP signaling pathway.
  Mol Cell Biochem, 334, 99.  
19819308 G.P.Demyanenko, A.I.Halberstadt, R.S.Rao, and P.F.Maness (2010).
CHL1 cooperates with PAK1-3 to regulate morphological differentiation of embryonic cortical neurons.
  Neuroscience, 165, 107-115.  
20237222 L.Kong, P.V.Lovell, A.Heger, C.V.Mello, and C.P.Ponting (2010).
Accelerated evolution of PAK3- and PIM1-like kinase gene families in the zebra finch, Taeniopygia guttata.
  Mol Biol Evol, 27, 1923-1934.  
20533885 S.B.Padrick, and M.K.Rosen (2010).
Physical mechanisms of signal integration by WASP family proteins.
  Annu Rev Biochem, 79, 707-735.  
20631255 S.W.Wallace, J.Durgan, D.Jin, and A.Hall (2010).
Cdc42 regulates apical junction formation in human bronchial epithelial cells through PAK4 and Par6B.
  Mol Biol Cell, 21, 2996-3006.  
  20927343 T.Otomo, D.R.Tomchick, C.Otomo, M.Machius, and M.K.Rosen (2010).
Crystal structure of the Formin mDia1 in autoinhibited conformation.
  PLoS One, 5, 0.
PDB code: 3obv
20124694 T.P.Ko, W.Y.Jeng, C.I.Liu, M.D.Lai, C.L.Wu, W.J.Chang, H.L.Shr, T.J.Lu, and A.H.Wang (2010).
Structures of human MST3 kinase in complex with adenine, ADP and Mn2+.
  Acta Crystallogr D Biol Crystallogr, 66, 145-154.  
20038798 V.Sauzeau, M.A.Sevilla, M.J.Montero, and X.R.Bustelo (2010).
The Rho/Rac exchange factor Vav2 controls nitric oxide-dependent responses in mouse vascular smooth muscle cells.
  J Clin Invest, 120, 315-330.  
20209159 Y.H.Hsu, and J.A.Traugh (2010).
Reciprocally coupled residues crucial for protein kinase Pak2 activity calculated by statistical coupling analysis.
  PLoS One, 5, e9455.  
20637424 Y.W.Ng, D.Raghunathan, P.M.Chan, Y.Baskaran, D.J.Smith, C.H.Lee, C.Verma, and E.Manser (2010).
Why an A-loop phospho-mimetic fails to activate PAK1: understanding an inaccessible kinase state by molecular dynamics simulations.
  Structure, 18, 879-890.  
19165420 B.Dummler, K.Ohshiro, R.Kumar, and J.Field (2009).
Pak protein kinases and their role in cancer.
  Cancer Metastasis Rev, 28, 51-63.  
19136554 C.Cheng, X.Kong, H.Wang, H.Gan, Y.Hao, W.Zou, J.Wu, Y.Chi, J.Yang, Y.Hong, K.Chen, and J.Gu (2009).
Trihydrophobin 1 Interacts with PAK1 and Regulates ERK/MAPK Activation and Cell Migration.
  J Biol Chem, 284, 8786-8796.  
19557173 C.M.Lightcap, G.Kari, L.E.Arias-Romero, J.Chernoff, U.Rodeck, and J.C.Williams (2009).
Interaction with LC8 is required for Pak1 nuclear import and is indispensable for zebrafish development.
  PLoS One, 4, e6025.  
19399514 E.Delpire (2009).
The mammalian family of sterile 20p-like protein kinases.
  Pflugers Arch, 458, 953-967.  
19160016 J.Eswaran, M.Soundararajan, and S.Knapp (2009).
Targeting group II PAKs in cancer and metastasis.
  Cancer Metastasis Rev, 28, 209-217.  
19723886 J.Viaud, and J.R.Peterson (2009).
An allosteric kinase inhibitor binds the p21-activated kinase autoregulatory domain covalently.
  Mol Cancer Ther, 8, 2559-2565.  
19445920 L.C.Chang, R.H.Lin, L.J.Huang, C.S.Chang, S.C.Kuo, and J.P.Wang (2009).
Inhibition of superoxide anion generation by CHS-111 via blockade of the p21-activated kinase, protein kinase B/Akt and protein kinase C signaling pathways in rat neutrophils.
  Eur J Pharmacol, 615, 207-217.  
19574218 M.C.Parrini, J.Camonis, M.Matsuda, and J.de Gunzburg (2009).
Dissecting activation of the PAK1 kinase at protrusions in living cells.
  J Biol Chem, 284, 24133-24143.  
19273597 M.Mitsushima, F.Toyoshima, and E.Nishida (2009).
Dual role of Cdc42 in spindle orientation control of adherent cells.
  Mol Cell Biol, 29, 2816-2827.  
19400716 M.O'Donnell, R.K.Chance, and G.J.Bashaw (2009).
Axon growth and guidance: receptor regulation and signal transduction.
  Annu Rev Neurosci, 32, 383-412.  
19465939 P.R.Molli, D.Q.Li, B.W.Murray, S.K.Rayala, and R.Kumar (2009).
PAK signaling in oncogenesis.
  Oncogene, 28, 2545-2555.  
19651772 R.Scholz, M.Suter, T.Weimann, C.Polge, P.V.Konarev, R.F.Thali, R.D.Tuerk, B.Viollet, T.Wallimann, U.Schlattner, and D.Neumann (2009).
Homo-oligomerization and activation of AMP-activated protein kinase are mediated by the kinase domain alphaG-helix.
  J Biol Chem, 284, 27425-27437.  
19120698 W.Wang, Y.Yang, Y.Gao, Q.Xu, F.Wang, S.Zhu, W.Old, K.Resing, N.Ahn, M.Lei, and X.Liu (2009).
Structural and mechanistic insights into Mps1 kinase activation.
  J Cell Mol Med, 13, 1679-1694.
PDB code: 3dbq
19141286 X.Min, R.Akella, H.He, J.M.Humphreys, S.E.Tsutakawa, S.J.Lee, J.A.Tainer, M.H.Cobb, and E.J.Goldsmith (2009).
The structure of the MAP2K MEK6 reveals an autoinhibitory dimer.
  Structure, 17, 96.
PDB code: 3enm
18427546 B.Maroto, M.B.Ye, K.von Lohneysen, A.Schnelzer, and U.G.Knaus (2008).
P21-activated kinase is required for mitotic progression and regulates Plk1.
  Oncogene, 27, 4900-4908.  
18650427 C.M.Lightcap, S.Sun, J.D.Lear, U.Rodeck, T.Polenova, and J.C.Williams (2008).
Biochemical and Structural Characterization of the Pak1-LC8 Interaction.
  J Biol Chem, 283, 27314-27324.
PDB codes: 3dvh 3dvp 3dvt
18668521 E.W.Bradley, M.M.Ruan, and M.J.Oursler (2008).
PAK1 is a novel MEK-independent raf target controlling expression of the IAP survivin in M-CSF-mediated osteoclast survival.
  J Cell Physiol, 217, 752-758.  
  18239191 H.Yao, S.R.Yang, I.Edirisinghe, S.Rajendrasozhan, S.Caito, D.Adenuga, M.A.O'Reilly, and I.Rahman (2008).
Disruption of p21 attenuates lung inflammation induced by cigarette smoke, LPS, and fMLP in mice.
  Am J Respir Cell Mol Biol, 39, 7.  
18184589 J.Eswaran, A.Bernad, J.M.Ligos, B.Guinea, J.E.Debreczeni, F.Sobott, S.A.Parker, R.Najmanovich, B.E.Turk, and S.Knapp (2008).
Structure of the human protein kinase MPSK1 reveals an atypical activation loop architecture.
  Structure, 16, 115-124.  
18639460 J.Eswaran, M.Soundararajan, R.Kumar, and S.Knapp (2008).
UnPAKing the class differences among p21-activated kinases.
  Trends Biochem Sci, 33, 394-403.  
18973295 J.Maksimoska, L.Feng, K.Harms, C.Yi, J.Kissil, R.Marmorstein, and E.Meggers (2008).
Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes.
  J Am Chem Soc, 130, 15764-15765.
PDB codes: 3fxz 3fy0
17910071 M.D.Jacobs, P.R.Caron, and B.J.Hare (2008).
Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations: structure of lck/imatinib complex.
  Proteins, 70, 1451-1460.
PDB code: 2pl0
18931661 M.Higuchi, K.Onishi, C.Kikuchi, and Y.Gotoh (2008).
Scaffolding function of PAK in the PDK1-Akt pathway.
  Nat Cell Biol, 10, 1356-1364.  
18649038 M.Nikolić (2008).
The Pak1 kinase: an important regulator of neuronal morphology and function in the developing forebrain.
  Mol Neurobiol, 37, 187-202.  
18650806 N.A.Sallee, G.M.Rivera, J.E.Dueber, D.Vasilescu, R.D.Mullins, B.J.Mayer, and W.A.Lim (2008).
The pathogen protein EspF(U) hijacks actin polymerization using mimicry and multivalency.
  Nature, 454, 1005-1008.  
18507705 P.Kreis, V.Rousseau, E.Thévenot, G.Combeau, and J.V.Barnier (2008).
The four mammalian splice variants encoded by the p21-activated kinase 3 gene have different biological properties.
  J Neurochem, 106, 1184-1197.  
18586681 P.M.Chan, L.Lim, and E.Manser (2008).
PAK Is Regulated by PI3K, PIX, CDC42, and PP2C{alpha} and Mediates Focal Adhesion Turnover in the Hyperosmotic Stress-induced p38 Pathway.
  J Biol Chem, 283, 24949-24961.  
  18392133 Q.Li, S.R.Mullins, B.F.Sloane, and R.R.Mattingly (2008).
p21-Activated kinase 1 coordinates aberrant cell survival and pericellular proteolysis in a three-dimensional culture model for premalignant progression of human breast cancer.
  Neoplasia, 10, 314-329.  
18510339 R.Anand, A.Y.Kim, M.Brent, and R.Marmorstein (2008).
Biochemical analysis of MST1 kinase: elucidation of a C-terminal regulatory region.
  Biochemistry, 47, 6719-6726.  
18642328 R.Kaur, X.Yuan, M.L.Lu, and S.P.Balk (2008).
Increased PAK6 expression in prostate cancer and identification of PAK6 associated proteins.
  Prostate, 68, 1510-1516.  
18984590 Y.H.Hsu, D.A.Johnson, and J.A.Traugh (2008).
Analysis of conformational changes during activation of protein kinase Pak2 by amide hydrogen/deuterium exchange.
  J Biol Chem, 283, 36397-36405.  
19351515 Y.Ke, M.Lei, and R.J.Solaro (2008).
Regulation of cardiac excitation and contraction by p21 activated kinase-1.
  Prog Biophys Mol Biol, 98, 238-250.  
19707468 Y.Ke, and R.J.Solaro (2008).
Use of a decoy peptide to purify p21 activated kinase-1 in cardiac muscle and identification of ceramide-related activation.
  Biologics, 2, 903-909.  
17620986 C.Flaiz, K.Kaempchen, C.Matthies, and C.O.Hanemann (2007).
Actin-rich protrusions and nonlocalized GTPase activation in Merlin-deficient schwannomas.
  J Neuropathol Exp Neurol, 66, 608-616.  
17254971 D.Guo, Y.C.Tan, D.Wang, K.S.Madhusoodanan, Y.Zheng, T.Maack, J.J.Zhang, and X.Y.Huang (2007).
A Rac-cGMP signaling pathway.
  Cell, 128, 341-355.  
17337635 E.M.Rubenstein, and M.C.Schmidt (2007).
Mechanisms regulating the protein kinases of Saccharomyces cerevisiae.
  Eukaryot Cell, 6, 571-583.  
17632506 F.Sananbenesi, A.Fischer, X.Wang, C.Schrick, R.Neve, J.Radulovic, and L.H.Tsai (2007).
A hippocampal Cdk5 pathway regulates extinction of contextual fear.
  Nat Neurosci, 10, 1012-1019.  
17912359 J.D.Knight, B.Qian, D.Baker, and R.Kothary (2007).
Conservation, variability and the modeling of active protein kinases.
  PLoS ONE, 2, e982.  
17292838 J.Eswaran, W.H.Lee, J.E.Debreczeni, P.Filippakopoulos, A.Turnbull, O.Fedorov, S.W.Deacon, J.R.Peterson, and S.Knapp (2007).
Crystal Structures of the p21-activated kinases PAK4, PAK5, and PAK6 reveal catalytic domain plasticity of active group II PAKs.
  Structure, 15, 201-213.
PDB codes: 2bva 2c30 2cdz 2f57
  17322107 J.Reutershan, R.Stockton, A.Zarbock, G.W.Sullivan, D.Chang, D.Scott, M.A.Schwartz, and K.Ley (2007).
Blocking p21-activated kinase reduces lipopolysaccharide-induced acute lung injury by preventing polymorphonuclear leukocyte infiltration.
  Am J Respir Crit Care Med, 175, 1027-1035.  
17726028 L.Rider, A.Shatrova, E.P.Feener, L.Webb, and M.Diakonova (2007).
JAK2 tyrosine kinase phosphorylates PAK1 and regulates PAK1 activity and functions.
  J Biol Chem, 282, 30985-30996.  
19804297 M.Lei, Y.Ke, and R.J.Solaro (2007).
Pak1: steps towards understanding the regulatory mechanisms of pacemaker function of the heart.
  Future Cardiol, 3, 473-476.  
17001318 M.Thullberg, A.Gad, A.Beeser, J.Chernoff, and S.Strömblad (2007).
The kinase-inhibitory domain of p21-activated kinase 1 (PAK1) inhibits cell cycle progression independent of PAK1 kinase activity.
  Oncogene, 26, 1820-1828.  
17537723 P.Kreis, E.Thévenot, V.Rousseau, B.Boda, D.Muller, and J.V.Barnier (2007).
The p21-activated kinase 3 implicated in mental retardation regulates spine morphogenesis through a Cdc42-dependent pathway.
  J Biol Chem, 282, 21497-21506.  
17289588 P.Sarkar, C.Reichman, T.Saleh, R.B.Birge, and C.G.Kalodimos (2007).
Proline cis-trans isomerization controls autoinhibition of a signaling protein.
  Mol Cell, 25, 413-426.  
17687038 T.Jacobs, F.Causeret, Y.V.Nishimura, M.Terao, A.Norman, M.Hoshino, and M.Nikolić (2007).
Localized activation of p21-activated kinase controls neuronal polarity and morphology.
  J Neurosci, 27, 8604-8615.  
17289663 Z.Wang, E.Oh, and D.C.Thurmond (2007).
Glucose-stimulated Cdc42 signaling is essential for the second phase of insulin secretion.
  J Biol Chem, 282, 9536-9546.  
16897755 A.Gringel, D.Walz, G.Rosenberger, A.Minden, K.Kutsche, P.Kopp, and S.Linder (2006).
PAK4 and alphaPIX determine podosome size and number in macrophages through localized actin regulation.
  J Cell Physiol, 209, 568-579.  
16293614 E.Torres, and M.K.Rosen (2006).
Protein-tyrosine kinase and GTPase signals cooperate to phosphorylate and activate Wiskott-Aldrich syndrome protein (WASP)/neuronal WASP.
  J Biol Chem, 281, 3513-3520.  
16607629 J.Szczepanowska, E.D.Korn, and H.Brzeska (2006).
Activation of myosin in HeLa cells causes redistribution of focal adhesions and F-actin from cell center to cell periphery.
  Cell Motil Cytoskeleton, 63, 356-374.  
16497167 M.Neumann, A.Foryst-Ludwig, S.Klar, K.Schweitzer, and M.Naumann (2006).
The PAK1 autoregulatory domain is required for interaction with NIK in Helicobacter pylori-induced NF-kappaB activation.
  Biol Chem, 387, 79-86.  
16413487 N.M.Alto, F.Shao, C.S.Lazar, R.L.Brost, G.Chua, S.Mattoo, S.A.McMahon, P.Ghosh, T.R.Hughes, C.Boone, and J.E.Dixon (2006).
Identification of a bacterial type III effector family with G protein mimicry functions.
  Cell, 124, 133-145.  
16723992 R.Kumar, A.E.Gururaj, and C.J.Barnes (2006).
p21-activated kinases in cancer.
  Nat Rev Cancer, 6, 459-471.  
16756506 R.P.Bhattacharyya, A.Reményi, B.J.Yeh, and W.A.Lim (2006).
Domains, motifs, and scaffolds: the role of modular interactions in the evolution and wiring of cell signaling circuits.
  Annu Rev Biochem, 75, 655-680.  
16581795 S.Cotteret, and J.Chernoff (2006).
Nucleocytoplasmic shuttling of Pak5 regulates its antiapoptotic properties.
  Mol Cell Biol, 26, 3215-3230.  
16380417 T.Kawasaki, H.Koita, T.Nakatsubo, K.Hasegawa, K.Wakabayashi, H.Takahashi, K.Umemura, T.Umezawa, and K.Shimamoto (2006).
Cinnamoyl-CoA reductase, a key enzyme in lignin biosynthesis, is an effector of small GTPase Rac in defense signaling in rice.
  Proc Natl Acad Sci U S A, 103, 230-235.  
15642175 A.E.Gururaj, S.K.Rayala, and R.Kumar (2005).
p21-activated kinase signaling in breast cancer.
  Breast Cancer Res, 7, 5.  
16194206 C.Soulet, B.Hechler, M.P.Gratacap, M.Plantavid, S.Offermanns, C.Gachet, and B.Payrastre (2005).
A differential role of the platelet ADP receptors P2Y1 and P2Y12 in Rac activation.
  J Thromb Haemost, 3, 2296-2306.  
16014608 D.Matenia, B.Griesshaber, X.Y.Li, A.Thiessen, C.Johne, J.Jiao, E.Mandelkow, and E.M.Mandelkow (2005).
PAK5 kinase is an inhibitor of MARK/Par-1, which leads to stable microtubules and dynamic actin.
  Mol Biol Cell, 16, 4410-4422.  
15821030 D.W.Leung, and M.K.Rosen (2005).
The nucleotide switch in Cdc42 modulates coupling between the GTPase-binding and allosteric equilibria of Wiskott-Aldrich syndrome protein.
  Proc Natl Acad Sci U S A, 102, 5685-5690.  
16244704 E.D.Scheeff, and P.E.Bourne (2005).
Structural evolution of the protein kinase-like superfamily.
  PLoS Comput Biol, 1, e49.  
16204230 J.H.Jung, and J.A.Traugh (2005).
Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141.
  J Biol Chem, 280, 40025-40031.  
16099876 K.D.Martyn, M.J.Kim, M.T.Quinn, M.C.Dinauer, and U.G.Knaus (2005).
p21-activated kinase (Pak) regulates NADPH oxidase activation in human neutrophils.
  Blood, 106, 3962-3969.  
15542607 L.J.Sundberg-Smith, J.T.Doherty, C.P.Mack, and J.M.Taylor (2005).
Adhesion stimulates direct PAK1/ERK2 association and leads to ERK-dependent PAK1 Thr212 phosphorylation.
  J Biol Chem, 280, 2055-2064.  
16292343 M.Lammers, R.Rose, A.Scrima, and A.Wittinghofer (2005).
The regulation of mDia1 by autoinhibition and its release by Rho*GTP.
  EMBO J, 24, 4176-4187.
PDB code: 2bap
15893667 M.Lei, M.A.Robinson, and S.C.Harrison (2005).
The active conformation of the PAK1 kinase domain.
  Structure, 13, 769-778.
PDB codes: 1yhv 1yhw
15550393 R.Kaur, X.Liu, O.Gjoerup, A.Zhang, X.Yuan, S.P.Balk, M.C.Schneider, and M.L.Lu (2005).
Activation of p21-activated kinase 6 by MAP kinase kinase 6 and p38 MAP kinase.
  J Biol Chem, 280, 3323-3330.  
16179248 S.S.Taylor, N.M.Haste, and G.Ghosh (2005).
PKR and eIF2alpha: integration of kinase dimerization, activation, and substrate docking.
  Cell, 122, 823-825.  
16061695 T.M.Leisner, M.Liu, Z.M.Jaffer, J.Chernoff, and L.V.Parise (2005).
Essential role of CIB1 in regulating PAK1 activation and cell migration.
  J Cell Biol, 170, 465-476.  
16253996 Y.Du, B.C.Böck, K.A.Schachter, M.Chao, and K.A.Gallo (2005).
Cdc42 induces activation loop phosphorylation and membrane targeting of mixed lineage kinase 3.
  J Biol Chem, 280, 42984-42993.  
15225553 C.DerMardirossian, A.Schnelzer, and G.M.Bokoch (2004).
Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase.
  Mol Cell, 15, 117-127.  
15292195 C.Weiss-Haljiti, C.Pasquali, H.Ji, C.Gillieron, C.Chabert, M.L.Curchod, E.Hirsch, A.J.Ridley, R.H.van Huijsduijnen, M.Camps, and C.Rommel (2004).
Involvement of phosphoinositide 3-kinase gamma, Rac, and PAK signaling in chemokine-induced macrophage migration.
  J Biol Chem, 279, 43273-43284.  
15047825 E.Krautkrämer, S.I.Giese, J.E.Gasteier, W.Muranyi, and O.T.Fackler (2004).
Human immunodeficiency virus type 1 Nef activates p21-activated kinase via recruitment into lipid rafts.
  J Virol, 78, 4085-4097.  
15023337 F.C.Peterson, R.R.Penkert, B.F.Volkman, and K.E.Prehoda (2004).
Cdc42 regulates the Par-6 PDZ domain through an allosteric CRIB-PDZ transition.
  Mol Cell, 13, 665-676.
PDB codes: 1ry4 1rzx
15308621 J.C.Lougheed, R.H.Chen, P.Mak, and T.J.Stout (2004).
Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1.
  J Biol Chem, 279, 44039-44045.
PDB codes: 1u46 1u4d 1u54
15542629 K.Pulkkinen, G.H.Renkema, F.Kirchhoff, and K.Saksela (2004).
Nef associates with p21-activated kinase 2 in a p21-GTPase-dependent dynamic activation complex within lipid rafts.
  J Virol, 78, 12773-12780.  
15469512 L.Leveleki, M.Mahlert, B.Sandrock, and M.Bölker (2004).
The PAK family kinase Cla4 is required for budding and morphogenesis in Ustilago maydis.
  Mol Microbiol, 54, 396-406.  
15471851 M.A.Koeppel, C.C.McCarthy, E.Moertl, and R.Jakobi (2004).
Identification and characterization of PS-GAP as a novel regulator of caspase-activated PAK-2.
  J Biol Chem, 279, 53653-53664.  
15182717 M.L.Hayashi, S.Y.Choi, B.S.Rao, H.Y.Jung, H.K.Lee, D.Zhang, S.Chattarji, A.Kirkwood, and S.Tonegawa (2004).
Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice.
  Neuron, 42, 773-787.  
14570903 M.Y.Niv, H.Rubin, J.Cohen, L.Tsirulnikov, T.Licht, A.Peretzman-Shemer, E.Cna'an, A.Tartakovsky, I.Stein, S.Albeck, I.Weinstein, M.Goldenberg-Furmanov, D.Tobi, E.Cohen, M.Laster, S.A.Ben-Sasson, and H.Reuveni (2004).
Sequence-based design of kinase inhibitors applicable for therapeutics and target identification.
  J Biol Chem, 279, 1242-1255.  
14660612 R.Dvorsky, L.Blumenstein, I.R.Vetter, and M.R.Ahmadian (2004).
Structural insights into the interaction of ROCKI with the switch regions of RhoA.
  J Biol Chem, 279, 7098-7104.
PDB code: 1s1c
15229651 S.K.Alahari, P.J.Reddig, and R.L.Juliano (2004).
The integrin-binding protein Nischarin regulates cell migration by inhibiting PAK.
  EMBO J, 23, 2777-2788.  
15483055 S.Lee, F.Rivero, K.C.Park, E.Huang, S.Funamoto, and R.A.Firtel (2004).
Dictyostelium PAKc is required for proper chemotaxis.
  Mol Biol Cell, 15, 5456-5469.  
15082779 T.H.Loo, Y.W.Ng, L.Lim, and E.Manser (2004).
GIT1 activates p21-activated kinase through a mechanism independent of p21 binding.
  Mol Cell Biol, 24, 3849-3859.  
14707132 W.Chen, M.Yazicioglu, and M.H.Cobb (2004).
Characterization of OSR1, a member of the mammalian Ste20p/germinal center kinase subfamily.
  J Biol Chem, 279, 11129-11136.  
15169762 W.Li, and K.L.Guan (2004).
The Down syndrome cell adhesion molecule (DSCAM) interacts with and activates Pak.
  J Biol Chem, 279, 32824-32831.  
  12906822 A.Farooq, L.Zeng, K.S.Yan, K.S.Ravichandran, and M.M.Zhou (2003).
Coupling of folding and binding in the PTB domain of the signaling protein Shc.
  Structure, 11, 905-913.
PDB codes: 1n3h 1oy2
12832486 A.J.Bardin, M.G.Boselli, and A.Amon (2003).
Mitotic exit regulation through distinct domains within the protein kinase Cdc15.
  Mol Cell Biol, 23, 5018-5030.  
14645531 C.Delaloy, J.Lu, A.M.Houot, S.Disse-Nicodeme, J.M.Gasc, P.Corvol, and X.Jeunemaitre (2003).
Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform.
  Mol Cell Biol, 23, 9208-9221.  
12581669 C.Herrmann (2003).
Ras-effector interactions: after one decade.
  Curr Opin Struct Biol, 13, 122-129.  
12640130 C.Xia, W.Ma, L.J.Stafford, C.Liu, L.Gong, J.F.Martin, and M.Liu (2003).
GGAPs, a new family of bifunctional GTP-binding and GTPase-activating proteins.
  Mol Cell Biol, 23, 2476-2488.  
14514689 D.Owen, P.N.Lowe, D.Nietlispach, C.E.Brosnan, D.Y.Chirgadze, P.J.Parker, T.L.Blundell, and H.R.Mott (2003).
Molecular dissection of the interaction between the small G proteins Rac1 and RhoA and protein kinase C-related kinase 1 (PRK1).
  J Biol Chem, 278, 50578-50587.
PDB code: 1urf
12877999 F.D.Ciccarelli, P.Bork, and E.Kerkhoff (2003).
The KIND module: a putative signalling domain evolved from the C lobe of the protein kinase fold.
  Trends Biochem Sci, 28, 349-352.  
14585966 G.L.Zhou, Y.Zhuo, C.C.King, B.H.Fryer, G.M.Bokoch, and J.Field (2003).
Akt phosphorylation of serine 21 on Pak1 modulates Nck binding and cell migration.
  Mol Cell Biol, 23, 8058-8069.  
12676796 G.M.Bokoch (2003).
Biology of the p21-activated kinases.
  Annu Rev Biochem, 72, 743-781.  
12865432 H.Chong, and K.L.Guan (2003).
Regulation of Raf through phosphorylation and N terminus-C terminus interaction.
  J Biol Chem, 278, 36269-36276.  
12907671 H.Wu, and Z.X.Wang (2003).
The mechanism of p21-activated kinase 2 autoactivation.
  J Biol Chem, 278, 41768-41778.  
  12586692 J.Ash, C.Wu, R.Larocque, M.Jamal, W.Stevens, M.Osborne, D.Y.Thomas, and M.Whiteway (2003).
Genetic analysis of the interface between Cdc42p and the CRIB domain of Ste20p in Saccharomyces cerevisiae.
  Genetics, 163, 9.  
12522133 L.A.Puto, K.Pestonjamasp, C.C.King, and G.M.Bokoch (2003).
p21-activated kinase 1 (PAK1) interacts with the Grb2 adapter protein to couple to growth factor signaling.
  J Biol Chem, 278, 9388-9393.  
14612425 M.C.Wilkes, S.J.Murphy, N.Garamszegi, and E.B.Leof (2003).
Cell-type-specific activation of PAK2 by transforming growth factor beta independent of Smad2 and Smad3.
  Mol Cell Biol, 23, 8878-8889.  
12588977 M.E.Keniry, and G.F.Sprague (2003).
Identification of p21-activated kinase specificity determinants in budding yeast: a single amino acid substitution imparts Ste20 specificity to Cla4.
  Mol Cell Biol, 23, 1569-1580.  
12409291 M.Endo, M.Shirouzu, and S.Yokoyama (2003).
The Cdc42 binding and scaffolding activities of the fission yeast adaptor protein Scd2.
  J Biol Chem, 278, 843-852.  
12912914 M.M.Zegers, M.A.Forget, J.Chernoff, K.E.Mostov, M.B.ter Beest, and S.H.Hansen (2003).
Pak1 and PIX regulate contact inhibition during epithelial wound healing.
  EMBO J, 22, 4155-4165.  
12586931 M.Ptashne, and A.Gann (2003).
Signal transduction. Imposing specificity on kinases.
  Science, 299, 1025-1027.  
12697809 P.M.Chan, S.Ilangumaran, J.La Rose, A.Chakrabartty, and R.Rottapel (2003).
Autoinhibition of the kit receptor tyrosine kinase by the cytosolic juxtamembrane region.
  Mol Cell Biol, 23, 3067-3078.  
12853446 R.Jakobi, C.C.McCarthy, M.A.Koeppel, and D.K.Stringer (2003).
Caspase-activated PAK-2 is regulated by subcellular targeting and proteasomal degradation.
  J Biol Chem, 278, 38675-38685.  
12897128 S.Cotteret, Z.M.Jaffer, A.Beeser, and J.Chernoff (2003).
p21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD.
  Mol Cell Biol, 23, 5526-5539.  
12606577 S.M.Garrard, C.T.Capaldo, L.Gao, M.K.Rosen, I.G.Macara, and D.R.Tomchick (2003).
Structure of Cdc42 in a complex with the GTPase-binding domain of the cell polarity protein, Par6.
  EMBO J, 22, 1125-1133.
PDB code: 1nf3
12954645 T.Shimizu, K.Ihara, R.Maesaki, M.Amano, K.Kaibuchi, and T.Hakoshima (2003).
Parallel coiled-coil association of the RhoA-binding domain in Rho-kinase.
  J Biol Chem, 278, 46046-46051.
PDB code: 1uix
12464619 V.Rousseau, O.Goupille, N.Morin, and J.V.Barnier (2003).
A new constitutively active brain PAK3 isoform displays modified specificities toward Rac and Cdc42 GTPases.
  J Biol Chem, 278, 3912-3920.  
12860998 Y.P.Ching, V.Y.Leong, C.M.Wong, and H.F.Kung (2003).
Identification of an autoinhibitory domain of p21-activated protein kinase 5.
  J Biol Chem, 278, 33621-33624.  
12560339 Z.Huang, J.Ling, and J.A.Traugh (2003).
Localization of p21-activated protein kinase gamma-PAK/Pak2 in the endoplasmic reticulum is required for induction of cytostasis.
  J Biol Chem, 278, 13101-13109.  
12887923 Z.Li, M.Hannigan, Z.Mo, B.Liu, W.Lu, Y.Wu, A.V.Smrcka, G.Wu, L.Li, M.Liu, C.K.Huang, and D.Wu (2003).
Directional sensing requires G beta gamma-mediated PAK1 and PIX alpha-dependent activation of Cdc42.
  Cell, 114, 215-227.  
14500727 Z.Tu, and F.S.Lee (2003).
Subdomain VIII is a specificity-determining region in MEKK1.
  J Biol Chem, 278, 48498-48505.  
12209132 A.J.Thrasher (2002).
WASp in immune-system organization and function.
  Nat Rev Immunol, 2, 635-646.  
12374799 B.E.Xu, X.Min, S.Stippec, B.H.Lee, E.J.Goldsmith, and M.H.Cobb (2002).
Regulation of WNK1 by an autoinhibitory domain and autophosphorylation.
  J Biol Chem, 277, 48456-48462.  
11864573 C.G.Koh, E.J.Tan, E.Manser, and L.Lim (2002).
The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family.
  Curr Biol, 12, 317-321.  
  12121643 E.J.Goldsmith, and C.I.Chang (2002).
Another twist in helix C and a missing pocket.
  Structure, 10, 888-889.  
12215529 G.H.Renkema, K.Pulkkinen, and K.Saksela (2002).
Cdc42/Rac1-mediated activation primes PAK2 for superactivation by tyrosine phosphorylation.
  Mol Cell Biol, 22, 6719-6725.  
11839490 H.J.Dyson, and P.E.Wright (2002).
Coupling of folding and binding for unstructured proteins.
  Curr Opin Struct Biol, 12, 54-60.  
12052864 H.Mita, J.Tsutsui, M.Takekawa, E.A.Witten, and H.Saito (2002).
Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory domain and GADD45 binding.
  Mol Cell Biol, 22, 4544-4555.  
12356872 H.Zhang, Z.Li, E.K.Viklund, and S.Strömblad (2002).
P21-activated kinase 4 interacts with integrin alpha v beta 5 and regulates alpha v beta 5-mediated cell migration.
  J Cell Biol, 158, 1287-1297.  
12456650 J.Souopgui, M.Sölter, and T.Pieler (2002).
XPak3 promotes cell cycle withdrawal during primary neurogenesis in Xenopus laevis.
  EMBO J, 21, 6429-6439.  
12006652 M.C.Brown, K.A.West, and C.E.Turner (2002).
Paxillin-dependent paxillin kinase linker and p21-activated kinase localization to focal adhesions involves a multistep activation pathway.
  Mol Biol Cell, 13, 1550-1565.  
11804587 M.C.Parrini, M.Lei, S.C.Harrison, and B.J.Mayer (2002).
Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1.
  Mol Cell, 9, 73-83.  
11950930 M.G.Lampugnani, A.Zanetti, F.Breviario, G.Balconi, F.Orsenigo, M.Corada, R.Spagnuolo, M.Betson, V.Braga, and E.Dejana (2002).
VE-cadherin regulates endothelial actin activating Rac and increasing membrane association of Tiam.
  Mol Biol Cell, 13, 1175-1189.  
12015977 M.Huse, and J.Kuriyan (2002).
The conformational plasticity of protein kinases.
  Cell, 109, 275-282.  
  11950591 M.Nikolic (2002).
The role of Rho GTPases and associated kinases in regulating neurite outgrowth.
  Int J Biochem Cell Biol, 34, 731-745.  
11733498 M.Zang, C.Hayne, and Z.Luo (2002).
Interaction between active Pak1 and Raf-1 is necessary for phosphorylation and activation of Raf-1.
  J Biol Chem, 277, 4395-4405.  
  12191603 R.A.Engh, and D.Bossemeyer (2002).
Structural aspects of protein kinase control-role of conformational flexibility.
  Pharmacol Ther, 93, 99.  
11792322 R.C.Deo, C.M.Groft, K.R.Rajashankar, and S.K.Burley (2002).
Recognition of the rotavirus mRNA 3' consensus by an asymmetric NSP3 homodimer.
  Cell, 108, 71-81.
PDB code: 1knz
11940652 R.E.Lamson, M.J.Winters, and P.M.Pryciak (2002).
Cdc42 regulation of kinase activity and signaling by the yeast p21-activated kinase Ste20.
  Mol Cell Biol, 22, 2939-2951.  
12384990 R.Kumar, and R.K.Vadlamudi (2002).
Emerging functions of p21-activated kinases in human cancer cells.
  J Cell Physiol, 193, 133-144.  
12177432 T.Xiao, K.H.Gardner, and S.R.Sprang (2002).
Cosolvent-induced transformation of a death domain tertiary structure.
  Proc Natl Acad Sci U S A, 99, 11151-11156.
PDB code: 1ik7
11839491 W.A.Lim (2002).
The modular logic of signaling proteins: building allosteric switches from simple binding domains.
  Curr Opin Struct Biol, 12, 61-68.  
12165471 Z.G.Luo, Q.Wang, J.Z.Zhou, J.Wang, Z.Luo, M.Liu, X.He, A.Wynshaw-Boris, W.C.Xiong, B.Lu, and L.Mei (2002).
Regulation of AChR clustering by Dishevelled interacting with MuSK and PAK1.
  Neuron, 35, 489-505.  
11259591 A.Chiloeches, C.S.Mason, and R.Marais (2001).
S338 phosphorylation of Raf-1 is independent of phosphatidylinositol 3-kinase and Pak3.
  Mol Cell Biol, 21, 2423-2434.  
11583620 C.H.Lin, B.J.Hare, G.Wagner, S.C.Harrison, T.Maniatis, and E.Fraenkel (2001).
A small domain of CBP/p300 binds diverse proteins: solution structure and functional studies.
  Mol Cell, 8, 581-590.
PDB code: 1jjs
11371639 C.Xia, W.Ma, L.J.Stafford, S.Marcus, W.C.Xiong, and M.Liu (2001).
Regulation of the p21-activated kinase (PAK) by a human Gbeta -like WD-repeat protein, hPIP1.
  Proc Natl Acad Sci U S A, 98, 6174-6179.  
11389841 C.Y.Chung, G.Potikyan, and R.A.Firtel (2001).
Control of cell polarity and chemotaxis by Akt/PKB and PI3 kinase through the regulation of PAKa.
  Mol Cell, 7, 937-947.  
11384750 E.Kerkhoff, and U.R.Rapp (2001).
The Ras-Raf relationship: an unfinished puzzle.
  Adv Enzyme Regul, 41, 261-267.  
11238883 F.Bi, B.Debreceni, K.Zhu, B.Salani, A.Eva, and Y.Zheng (2001).
Autoinhibition mechanism of proto-Dbl.
  Mol Cell Biol, 21, 1463-1474.  
11438672 G.Buchwald, E.Hostinova, M.G.Rudolph, A.Kraemer, A.Sickmann, H.E.Meyer, K.Scheffzek, and A.Wittinghofer (2001).
Conformational switch and role of phosphorylation in PAK activation.
  Mol Cell Biol, 21, 5179-5189.  
11160719 G.H.Renkema, A.Manninen, and K.Saksela (2001).
Human immunodeficiency virus type 1 Nef selectively associates with a catalytically active subpopulation of p21-activated kinase 2 (PAK2) independently of PAK2 binding to Nck or beta-PIX.
  J Virol, 75, 2154-2160.  
11579107 H.Brzeska, R.Young, C.Tan, J.Szczepanowska, and E.D.Korn (2001).
Calmodulin-binding and autoinhibitory domains of Acanthamoeba myosin I heavy chain kinase, a p21-activated kinase (PAK).
  J Biol Chem, 276, 47468-47473.  
11395421 H.G.Dohlman, and J.W.Thorner (2001).
Regulation of G protein-initiated signal transduction in yeast: paradigms and principles.
  Annu Rev Biochem, 70, 703-754.  
11604137 H.Hu, T.F.Marton, and C.S.Goodman (2001).
Plexin B mediates axon guidance in Drosophila by simultaneously inhibiting active Rac and enhancing RhoA signaling.
  Neuron, 32, 39-51.  
11701921 I.R.Vetter, and A.Wittinghofer (2001).
The guanine nucleotide-binding switch in three dimensions.
  Science, 294, 1299-1304.  
11283256 I.Tan, K.T.Seow, L.Lim, and T.Leung (2001).
Intermolecular and intramolecular interactions regulate catalytic activity of myotonic dystrophy kinase-related Cdc42-binding kinase alpha.
  Mol Cell Biol, 21, 2767-2778.  
  11709168 K.Scheffzek, P.Grünewald, S.Wohlgemuth, W.Kabsch, H.Tu, M.Wigler, A.Wittinghofer, and C.Herrmann (2001).
The Ras-Byr2RBD complex: structural basis for Ras effector recognition in yeast.
  Structure, 9, 1043-1050.
PDB code: 1k8r
11134331 K.Zhu, B.Debreceni, F.Bi, and Y.Zheng (2001).
Oligomerization of DH domain is essential for Dbl-induced transformation.
  Mol Cell Biol, 21, 425-437.  
10966102 G.R.Hoffman, and R.A.Cerione (2000).
Flipping the switch: the structural basis for signaling through the CRIB motif.
  Cell, 102, 403-406.  
11121037 J.Roig, P.T.Tuazon, P.A.Zipfel, A.M.Pendergast, and J.A.Traugh (2000).
Functional interaction between c-Abl and the p21-activated protein kinase gamma-PAK.
  Proc Natl Acad Sci U S A, 97, 14346-14351.  
10995436 R.Rohatgi, H.Y.Ho, and M.W.Kirschner (2000).
Mechanism of N-WASP activation by CDC42 and phosphatidylinositol 4, 5-bisphosphate.
  J Cell Biol, 150, 1299-1310.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.