General Information of Target

Target ID LDTP05769
Target Name Serine/threonine-protein kinase PAK 1 (PAK1)
Gene Name PAK1
Gene ID 5058
Synonyms
Serine/threonine-protein kinase PAK 1; EC 2.7.11.1; Alpha-PAK; p21-activated kinase 1; PAK-1; p65-PAK
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Sequence
MSNNGLDIQDKPPAPPMRNTSTMIGAGSKDAGTLNHGSKPLPPNPEEKKKKDRFYRSILP
GDKTNKKKEKERPEISLPSDFEHTIHVGFDAVTGEFTGMPEQWARLLQTSNITKSEQKKN
PQAVLDVLEFYNSKKTSNSQKYMSFTDKSAEDYNSSNALNVKAVSETPAVPPVSEDEDDD
DDDATPPPVIAPRPEHTKSVYTRSVIEPLPVTPTRDVATSPISPTENNTTPPDALTRNTE
KQKKKPKMSDEEILEKLRSIVSVGDPKKKYTRFEKIGQGASGTVYTAMDVATGQEVAIKQ
MNLQQQPKKELIINEILVMRENKNPNIVNYLDSYLVGDELWVVMEYLAGGSLTDVVTETC
MDEGQIAAVCRECLQALEFLHSNQVIHRDIKSDNILLGMDGSVKLTDFGFCAQITPEQSK
RSTMVGTPYWMAPEVVTRKAYGPKVDIWSLGIMAIEMIEGEPPYLNENPLRALYLIATNG
TPELQNPEKLSAIFRDFLNRCLEMDVEKRGSAKELLQHQFLKIAKPLSSLTPLIAAAKEA
TKNNH
Target Type
Literature-reported
Target Bioclass
Enzyme
Family
Protein kinase superfamily, STE Ser/Thr protein kinase family, STE20 subfamily
Subcellular location
Cytoplasm
Function
Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as a GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2. Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. Required for atypical chemokine receptor ACKR2-induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation. Plays a role in RUFY3-mediated facilitating gastric cancer cells migration and invasion. In response to DNA damage, phosphorylates MORC2 which activates its ATPase activity and facilitates chromatin remodeling. In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in F-actin stabilization. In hippocampal neurons, necessary for the formation of dendritic spines and excitatory synapses; this function is dependent on kinase activity and may be exerted by the regulation of actomyosin contractility through the phosphorylation of myosin II regulatory light chain (MLC). Along with GIT1, positively regulates microtubule nucleation during interphase. Phosphorylates FXR1, promoting its localization to stress granules and activity.
TTD ID
T37961
Uniprot ID
Q13153
DrugMap ID
TTFN95D
Ensemble ID
ENST00000278568.8
HGNC ID
HGNC:8590
ChEMBL ID
CHEMBL4600

Target Site Mutations in Different Cell Lines

Cell line Mutation details Probe for labeling this protein in this cell
HT115 SNV: p.N111H .
MFE319 SNV: p.D505G .
SUPT1 SNV: p.V403A .

Probe(s) Labeling This Target

ABPP Probe
Click To Hide/Show 13 Probe Related to This Target
Probe name Structure Binding Site(Ratio) Interaction ID Ref
TH211
 Probe Info 
Y153(10.03)  LDD0257  [1]
DBIA
 Probe Info 
C373(1.43)  LDD3312  [2]
HHS-475
 Probe Info 
Y131(0.92)  LDD0264  [3]
HHS-465
 Probe Info 
Y131(5.51)  LDD2237  [4]
4-Iodoacetamidophenylacetylene
 Probe Info 
N.A.  LDD0038  [5]
IA-alkyne
 Probe Info 
N.A.  LDD0032  [6]
IPIAA_H
 Probe Info 
N.A.  LDD0030  [7]
IPIAA_L
 Probe Info 
N.A.  LDD0031  [7]
Lodoacetamide azide
 Probe Info 
N.A.  LDD0037  [5]
TFBX
 Probe Info 
N.A.  LDD0027  [8]
IPM
 Probe Info 
N.A.  LDD2156  [9]
Acrolein
 Probe Info 
N.A.  LDD0217  [10]
NAIA_5
 Probe Info 
N.A.  LDD2223  [11]
PAL-AfBPP Probe
Click To Hide/Show 3 Probe Related to This Target
Probe name Structure Binding Site(Ratio) Interaction ID Ref
C210
 Probe Info 
44.63  LDD1884  [12]
C289
 Probe Info 
36.25  LDD1959  [12]
C403
 Probe Info 
13.83  LDD2061  [12]

Competitor(s) Related to This Target

Competitor ID Name Cell line Binding Site(Ratio) Interaction ID Ref
 LDCM0108  Chloroacetamide HeLa N.A.  LDD0222  [10]
 LDCM0625  F8 Ramos C501(0.78); C411(0.87)  LDD2187  [13]
 LDCM0572  Fragment10 Ramos C501(0.64); C411(0.86)  LDD2189  [13]
 LDCM0573  Fragment11 Ramos C501(0.10); C411(0.31)  LDD2190  [13]
 LDCM0574  Fragment12 Ramos C501(0.87); C411(0.91)  LDD2191  [13]
 LDCM0575  Fragment13 Ramos C501(1.12); C411(1.09)  LDD2192  [13]
 LDCM0576  Fragment14 Ramos C501(0.70); C411(1.00)  LDD2193  [13]
 LDCM0579  Fragment20 Ramos C501(0.89); C411(0.92)  LDD2194  [13]
 LDCM0580  Fragment21 Ramos C501(0.84); C411(1.32)  LDD2195  [13]
 LDCM0582  Fragment23 Ramos C501(0.98); C411(1.74)  LDD2196  [13]
 LDCM0578  Fragment27 Ramos C501(0.90); C411(0.98)  LDD2197  [13]
 LDCM0586  Fragment28 Ramos C501(0.85); C411(1.44)  LDD2198  [13]
 LDCM0588  Fragment30 Ramos C501(1.24); C411(1.07)  LDD2199  [13]
 LDCM0589  Fragment31 Ramos C501(1.17); C411(1.57)  LDD2200  [13]
 LDCM0590  Fragment32 Ramos C501(0.67); C411(0.88)  LDD2201  [13]
 LDCM0468  Fragment33 Ramos C501(1.13); C411(0.97)  LDD2202  [13]
 LDCM0596  Fragment38 Ramos C501(1.46); C411(1.00)  LDD2203  [13]
 LDCM0566  Fragment4 Ramos C501(0.79); C411(1.02)  LDD2184  [13]
 LDCM0610  Fragment52 Ramos C501(1.66); C411(0.69)  LDD2204  [13]
 LDCM0614  Fragment56 Ramos C501(1.62); C411(0.95)  LDD2205  [13]
 LDCM0569  Fragment7 Ramos C501(0.68); C411(0.78)  LDD2186  [13]
 LDCM0571  Fragment9 Ramos C501(0.64); C411(0.75)  LDD2188  [13]
 LDCM0116  HHS-0101 DM93 Y131(0.92)  LDD0264  [3]
 LDCM0117  HHS-0201 DM93 Y131(0.60)  LDD0265  [3]
 LDCM0118  HHS-0301 DM93 Y131(0.72)  LDD0266  [3]
 LDCM0119  HHS-0401 DM93 Y131(1.02)  LDD0267  [3]
 LDCM0120  HHS-0701 DM93 Y131(0.75)  LDD0268  [3]
 LDCM0107  IAA HeLa N.A.  LDD0221  [10]
 LDCM0022  KB02 Ramos C501(0.63); C411(0.67)  LDD2182  [13]
 LDCM0023  KB03 Ramos C501(0.77); C411(0.86)  LDD2183  [13]
 LDCM0024  KB05 HMCB C373(1.43)  LDD3312  [2]

The Interaction Atlas With This Target

The Protein(s) Related To This Target

Enzyme
Click To Hide/Show 11 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Alpha-adducin (ADD1) Aldolase class II family P35611
Lysosomal acid phosphatase (ACP2) Histidine acid phosphatase family P11117
Cyclin-dependent kinase 11B (CDK11B) CMGC Ser/Thr protein kinase family P21127
Mitogen-activated protein kinase 11 (MAPK11) CMGC Ser/Thr protein kinase family Q15759
LIM domain kinase 1 (LIMK1) TKL Ser/Thr protein kinase family P53667
GTP-binding protein Rit1 (RIT1) Ras family Q92963
Ras-related C3 botulinum toxin substrate 1 (RAC1) Rho family P63000
Rho-related GTP-binding protein RhoJ (RHOJ) Rho family Q9H4E5
Rho-related GTP-binding protein RhoU (RHOU) Rho family Q7L0Q8
Cell division control protein 42 homolog (CDC42) Rho family P60953
SPRY domain-containing SOCS box protein 1 (SPSB1) SPSB family Q96BD6
Transporter and channel
Click To Hide/Show 1 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Mitochondrial import inner membrane translocase subunit Tim17-B (TIMM17B) Tim17/Tim22/Tim23 family O60830
Transcription factor
Click To Hide/Show 1 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Zinc fingers and homeoboxes protein 1, isoform 2 (ZHX1-C8orf76) . Q96EF9
Other
Click To Hide/Show 15 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Dynein light chain 1, cytoplasmic (DYNLL1) Dynein light chain family P63167
Kelch-like ECH-associated protein 1 (KEAP1) KEAP1 family Q14145
Syntaxin-11 (STX11) Syntaxin family O75558
T-complex protein 10A homolog 1 (TCP10L) TCP10 family Q8TDR4
TSSK6-activating co-chaperone protein (TSACC) TSACC family Q96A04
ARF GTPase-activating protein GIT1 (GIT1) . Q9Y2X7
ARF GTPase-activating protein GIT2 (GIT2) . Q14161
Cytoplasmic protein NCK2 (NCK2) . O43639
Kelch-like protein 20 (KLHL20) . Q9Y2M5
Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) . Q9Y239
Poly(rC)-binding protein 1 (PCBP1) . Q15365
Rho guanine nucleotide exchange factor 6 (ARHGEF6) . Q15052
Rho guanine nucleotide exchange factor 7 (ARHGEF7) . Q14155
Telethonin (TCAP) . O15273
Testis-expressed protein 12 (TEX12) . Q9BXU0

The Drug(s) Related To This Target

Approved
Click To Hide/Show 1 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
Fostamatinib Small molecular drug DB12010
Investigative
Click To Hide/Show 3 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
Il-94 Small molecular drug D07ORL
Pmid20005102c1 Small molecular drug D0L2WP
Rki-1447 Small molecular drug D03CPB

References

1 Chemoproteomic profiling of kinases in live cells using electrophilic sulfonyl triazole probes. Chem Sci. 2021 Jan 21;12(9):3295-3307. doi: 10.1039/d0sc06623k.
2 DrugMap: A quantitative pan-cancer analysis of cysteine ligandability. Cell. 2024 May 9;187(10):2536-2556.e30. doi: 10.1016/j.cell.2024.03.027. Epub 2024 Apr 22.
Mass spectrometry data entry: PXD047840
3 Discovery of a Cell-Active SuTEx Ligand of Prostaglandin Reductase 2. Chembiochem. 2021 Jun 15;22(12):2134-2139. doi: 10.1002/cbic.202000879. Epub 2021 Apr 29.
4 Global targeting of functional tyrosines using sulfur-triazole exchange chemistry. Nat Chem Biol. 2020 Feb;16(2):150-159. doi: 10.1038/s41589-019-0404-5. Epub 2019 Nov 25.
5 Enhancing Cysteine Chemoproteomic Coverage through Systematic Assessment of Click Chemistry Product Fragmentation. Anal Chem. 2022 Mar 8;94(9):3800-3810. doi: 10.1021/acs.analchem.1c04402. Epub 2022 Feb 23.
Mass spectrometry data entry: PXD028853
6 SP3-FAIMS Chemoproteomics for High-Coverage Profiling of the Human Cysteinome*. Chembiochem. 2021 May 14;22(10):1841-1851. doi: 10.1002/cbic.202000870. Epub 2021 Feb 18.
Mass spectrometry data entry: PXD023056 , PXD023059 , PXD023058 , PXD023057 , PXD023060
7 SP3-Enabled Rapid and High Coverage Chemoproteomic Identification of Cell-State-Dependent Redox-Sensitive Cysteines. Mol Cell Proteomics. 2022 Apr;21(4):100218. doi: 10.1016/j.mcpro.2022.100218. Epub 2022 Feb 25.
Mass spectrometry data entry: PXD029500 , PXD031647
8 Chemoproteomic Profiling by Cysteine Fluoroalkylation Reveals Myrocin G as an Inhibitor of the Nonhomologous End Joining DNA Repair Pathway. J Am Chem Soc. 2021 Dec 8;143(48):20332-20342. doi: 10.1021/jacs.1c09724. Epub 2021 Nov 24.
Mass spectrometry data entry: PXD029255
9 Benchmarking Cleavable Biotin Tags for Peptide-Centric Chemoproteomics. J Proteome Res. 2022 May 6;21(5):1349-1358. doi: 10.1021/acs.jproteome.2c00174. Epub 2022 Apr 25.
Mass spectrometry data entry: PXD031019
10 ACR-Based Probe for the Quantitative Profiling of Histidine Reactivity in the Human Proteome. J Am Chem Soc. 2023 Mar 8;145(9):5252-5260. doi: 10.1021/jacs.2c12653. Epub 2023 Feb 27.
11 N-Acryloylindole-alkyne (NAIA) enables imaging and profiling new ligandable cysteines and oxidized thiols by chemoproteomics. Nat Commun. 2023 Jun 15;14(1):3564. doi: 10.1038/s41467-023-39268-w.
Mass spectrometry data entry: PXD041264
12 Large-scale chemoproteomics expedites ligand discovery and predicts ligand behavior in cells. Science. 2024 Apr 26;384(6694):eadk5864. doi: 10.1126/science.adk5864. Epub 2024 Apr 26.
Mass spectrometry data entry: PXD041587
13 Site-specific quantitative cysteine profiling with data-independent acquisition-based mass spectrometry. Methods Enzymol. 2023;679:295-322. doi: 10.1016/bs.mie.2022.07.037. Epub 2022 Sep 7.
Mass spectrometry data entry: PXD027578