Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXXSJ53)

• DOT Name: Progranulin (GRN)
• Synonyms: PGRN; Acrogranin; Epithelin precursor; Glycoprotein of 88 Kda; GP88; Glycoprotein 88; Granulin precursor; PC cell-derived growth factor; PCDGF; Proepithelin; PEPI
• Gene Name: GRN
• Related Disease:
  Frontotemporal dementia and/or amyotrophic lateral sclerosis
  Neuronal ceroid lipofuscinosis
  GRN-related frontotemporal lobar degeneration with Tdp43 inclusions
  Neuronal ceroid lipofuscinosis 11
• UniProt ID: GRN_HUMAN
• PDB ID: 1G26; 2JYE; 2JYT; 2JYU; 2JYV; 6NUG
• Pfam ID: PF00396
• Sequence:
  MWTLVSWVALTAGLVAGTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGP
  CQVDAHCSAGHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNS
  VGAIQCPDSQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTRCIT
  PTGTHPLAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNATCC
  SDHLHCCPQDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYTCCRLQ
  SGAWGCCPFTQAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHLSLPDPQAL
  KRDVPCDNVSSCPSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTCVAEGQCQRGS
  EIVAGLEKMPARRASLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLPHAVCCEDRQH
  CCPAGYTCNVKARSCEKEVVSAQPATFLARSPHVGVKDVECGEGHFCHDNQTCCRDNRQG
  WACCPYRQGVCCADRRHCCPAGFRCAARGTKCLRREAPRWDAPLRDPALRQLL
• Function: Secreted protein that acts as a key regulator of lysosomal function and as a growth factor involved in inflammation, wound healing and cell proliferation. Regulates protein trafficking to lysosomes and, also the activity of lysosomal enzymes. Facilitates also the acidification of lysosomes, causing degradation of mature CTSD by CTSB. In addition, functions as a wound-related growth factor that acts directly on dermal fibroblasts and endothelial cells to promote division, migration and the formation of capillary-like tubule structures. Also promotes epithelial cell proliferation by blocking TNF-mediated neutrophil activation preventing release of oxidants and proteases. Moreover, modulates inflammation in neurons by preserving neurons survival, axonal outgrowth and neuronal integrity ; [Granulin-4]: Promotes proliferation of the epithelial cell line A431 in culture.; [Granulin-3]: Inhibits epithelial cell proliferation and induces epithelial cells to secrete IL-8; [Granulin-7]: Stabilizes CTSD through interaction with CTSD leading to maintain its aspartic-type peptidase activity.
• Tissue Specificity: In myelogenous leukemic cell lines of promonocytic, promyelocytic, and proerythroid lineage, in fibroblasts, and very strongly in epithelial cell lines. Present in inflammatory cells and bone marrow. Highest levels in kidney.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Frontotemporal dementia and/or amyotrophic lateral sclerosis	DIS2B7L2	Definitive	Autosomal dominant	[1]
Neuronal ceroid lipofuscinosis	DIS9A4K4	Definitive	Autosomal recessive	[1]
GRN-related frontotemporal lobar degeneration with Tdp43 inclusions	DIS6Z6TF	Strong	Autosomal dominant	[2]
Neuronal ceroid lipofuscinosis 11	DISEL5G3	Strong	Autosomal recessive	[3]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Progranulin (GRN) affects the response to substance of Methotrexate.	[30]
Dexamethasone	DMMWZET	Approved	Progranulin (GRN) decreases the response to substance of Dexamethasone.	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Progranulin (GRN).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Progranulin (GRN).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Progranulin (GRN).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Progranulin (GRN).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Progranulin (GRN).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Progranulin (GRN).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Progranulin (GRN).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Progranulin (GRN).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Progranulin (GRN).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Progranulin (GRN).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Progranulin (GRN).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Progranulin (GRN).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Progranulin (GRN).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Progranulin (GRN).	[15]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Progranulin (GRN).	[16]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Progranulin (GRN).	[17]
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the expression of Progranulin (GRN).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Progranulin (GRN).	[18]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Progranulin (GRN).	[19]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Progranulin (GRN).	[6]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Progranulin (GRN).	[19]
Guaiacol	DMN4E7T	Phase 3	Guaiacol increases the expression of Progranulin (GRN).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Progranulin (GRN).	[14]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Progranulin (GRN).	[20]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Progranulin (GRN).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Progranulin (GRN).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Progranulin (GRN).	[25]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Progranulin (GRN).	[26]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Progranulin (GRN).	[27]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Progranulin (GRN).	[28]
Rutin	DMEHRAJ	Investigative	Rutin increases the expression of Progranulin (GRN).	[29]
CATECHIN	DMY38SB	Investigative	CATECHIN increases the expression of Progranulin (GRN).	[29]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid increases the expression of Progranulin (GRN).	[19]

References

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