Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLUNCIH)

• DOT Name: Serine/threonine-protein kinase PAK 2 (PAK2)
• Synonyms: EC 2.7.11.1; Gamma-PAK; PAK65; S6/H4 kinase; p21-activated kinase 2; PAK-2; p58
• Gene Name: PAK2
• Related Disease: Knobloch syndrome 2
• UniProt ID: PAK2_HUMAN
• PDB ID: 3PCS
• EC Number: 2.7.11.1
• Pfam ID: PF00786 ; PF00069
• Sequence:
  MSDNGELEDKPPAPPVRMSSTIFSTGGKDPLSANHSLKPLPSVPEEKKPRHKIISIFSGT
  EKGSKKKEKERPEISPPSDFEHTIHVGFDAVTGEFTGMPEQWARLLQTSNITKLEQKKNP
  QAVLDVLKFYDSNTVKQKYLSFTPPEKDGFPSGTPALNAKGTEAPAVVTEEEDDDEETAP
  PVIAPRPDHTKSIYTRSVIDPVPAPVGDSHVDGAAKSLDKQKKKTKMTDEEIMEKLRTIV
  SIGDPKKKYTRYEKIGQGASGTVFTATDVALGQEVAIKQINLQKQPKKELIINEILVMKE
  LKNPNIVNFLDSYLVGDELFVVMEYLAGGSLTDVVTETCMDEAQIAAVCRECLQALEFLH
  ANQVIHRDIKSDNVLLGMEGSVKLTDFGFCAQITPEQSKRSTMVGTPYWMAPEVVTRKAY
  GPKVDIWSLGIMAIEMVEGEPPYLNENPLRALYLIATNGTPELQNPEKLSPIFRDFLNRC
  LEMDVEKRGSAKELLQHPFLKLAKPLSSLTPLIMAAKEAMKSNR
• Function: 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 a 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. Phosphorylates CASP7, thereby preventing its activity. 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.
• Tissue Specificity: Ubiquitously expressed. Higher levels seen in skeletal muscle, ovary, thymus and spleen.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  ErbB sig.ling pathway (hsa04012)
  Ras sig.ling pathway (hsa04014)
  Axon guidance (hsa04360)
  Focal adhesion (hsa04510)
  T cell receptor sig.ling pathway (hsa04660)
  Regulation of actin cytoskeleton (hsa04810)
  Pathogenic Escherichia coli infection (hsa05130)
  Human immunodeficiency virus 1 infection (hsa05170)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway:
  Generation of second messenger molecules (R-HSA-202433)
  Regulation of PAK-2p34 activity by PS-GAP/RHG10 (R-HSA-211728)
  Regulation of activated PAK-2p34 by proteasome mediated degradation (R-HSA-211733)
  Stimulation of the cell death response by PAK-2p34 (R-HSA-211736)
  FCERI mediated MAPK activation (R-HSA-2871796)
  CD28 dependent Vav1 pathway (R-HSA-389359)
  Ephrin signaling (R-HSA-3928664)
  Sema3A PAK dependent Axon repulsion (R-HSA-399954)
  Activation of RAC1 (R-HSA-428540)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  Smooth Muscle Contraction (R-HSA-445355)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  CD209 (DC-SIGN) signaling (R-HSA-5621575)
  RHO GTPases activate PAKs (R-HSA-5627123)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation (R-HSA-8950505)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOH GTPase cycle (R-HSA-9013407)
  RHOG GTPase cycle (R-HSA-9013408)
  RHOJ GTPase cycle (R-HSA-9013409)
  RHOU GTPase cycle (R-HSA-9013420)
  RAC3 GTPase cycle (R-HSA-9013423)
  RHOV GTPase cycle (R-HSA-9013424)
  Nef and signal transduction (R-HSA-164944)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Knobloch syndrome 2	DISK88G8	Limited	Unknown	[1]

6 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Serine/threonine-protein kinase PAK 2 (PAK2).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Serine/threonine-protein kinase PAK 2 (PAK2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Serine/threonine-protein kinase PAK 2 (PAK2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Serine/threonine-protein kinase PAK 2 (PAK2).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Serine/threonine-protein kinase PAK 2 (PAK2).	[19]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Serine/threonine-protein kinase PAK 2 (PAK2).	[20]

15 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[11]
Marinol	DM70IK5	Approved	Marinol increases the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[12]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[10]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[13]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[4]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the activity of Serine/threonine-protein kinase PAK 2 (PAK2).	[17]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Serine/threonine-protein kinase PAK 2 (PAK2).	[21]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Curcumin	DMQPH29	Phase 3	Curcumin decreases the cleavage of Serine/threonine-protein kinase PAK 2 (PAK2).	[14]

References

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