Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX9WN2E)

• DOT Name: RAS guanyl-releasing protein 1 (RASGRP1)
• Synonyms: Calcium and DAG-regulated guanine nucleotide exchange factor II; CalDAG-GEFII; Ras guanyl-releasing protein
• Gene Name: RASGRP1
• Related Disease:
  Bipolar disorder
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Adult lymphoma
  Attention deficit hyperactivity disorder
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Autoimmune lymphoproliferative syndrome type 1
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Hyperglycemia
  Hypothyroidism
  IgA nephropathy
  Immunodeficiency
  Immunodeficiency 64
  Lymphoma
  Lymphoproliferative syndrome
  Multiple sclerosis
  Neoplasm
  Pediatric lymphoma
  Pelvic inflammatory disease
  Rheumatoid arthritis
  STAT3-related early-onset multisystem autoimmune disease
  Systemic lupus erythematosus
  T-cell acute lymphoblastic leukaemia
  T-cell leukaemia
  T-cell lymphoma
  Thrombocytopenia
  Triple negative breast cancer
  Type-1 diabetes
  Type-1/2 diabetes
  Advanced cancer
  Colorectal carcinoma
  Crohn disease
  Epidermodysplasia verruciformis
  Hashimoto thyroiditis
  Inherited bleeding disorder, platelet-type
  Autoimmune lymphoproliferative syndrome
  Endometriosis
  Classic Hodgkin lymphoma
  Epstein barr virus infection
  Microphthalmia
  Non-insulin dependent diabetes
• UniProt ID: GRP1_HUMAN
• PDB ID: 4L9M; 4L9U
• Pfam ID: PF00130 ; PF00617 ; PF00618
• Sequence:
  MGTLGKAREAPRKPSHGCRAASKARLEAKPANSPFPSHPSLAHITQFRMMVSLGHLAKGA
  SLDDLIDSCIQSFDADGNLCRSNQLLQVMLTMHRIVISSAELLQKVITLYKDALAKNSPG
  LCLKICYFVRYWITEFWVMFKMDASLTDTMEEFQELVKAKGEELHCRLIDTTQINARDWS
  RKLTQRIKSNTSKKRKVSLLFDHLEPEELSEHLTYLEFKSFRRISFSDYQNYLVNSCVKE
  NPTMERSIALCNGISQWVQLMVLSRPTPQLRAEVFIKFIQVAQKLHQLQNFNTLMAVIGG
  LCHSSISRLKETSSHVPHEINKVLGEMTELLSSSRNYDNYRRAYGECTDFKIPILGVHLK
  DLISLYEAMPDYLEDGKVNVHKLLALYNHISELVQLQEVAPPLEANKDLVHLLTLSLDLY
  YTEDEIYELSYAREPRNHRAPPLTPSKPPVVVDWASGVSPKPDPKTISKHVQRMVDSVFK
  NYDHDQDGYISQEEFEKIAASFPFSFCVMDKDREGLISRDEITAYFMRASSIYSKLGLGF
  PHNFQETTYLKPTFCDNCAGFLWGVIKQGYRCKDCGMNCHKQCKDLVVFECKKRAKNPVA
  PTENNTSVGPVSNLCSLGAKDLLHAPEEGPFTFPNGEAVEHGEESKDRTIMLMGVSSQKI
  SLRLKRAVAHKATQTESQPWIGSEGPSGPFVLSSPRKTAQDTLYVLPSPTSPCPSPVLVR
  KRAFVKWENKDSLIKSKEELRHLRLPTYQELEQEINTLKADNDALKIQLKYAQKKIESLQ
  LEKSNHVLAQMEQGDCS
• Function: Functions as a calcium- and diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP. Activates the Erk/MAP kinase cascade. Regulates T-cell/B-cell development, homeostasis and differentiation by coupling T-lymphocyte/B-lymphocyte antigen receptors to Ras. Regulates NK cell cytotoxicity and ITAM-dependent cytokine production by activation of Ras-mediated ERK and JNK pathways. Functions in mast cell degranulation and cytokine secretion, regulating FcERI-evoked allergic responses. May also function in differentiation of other cell types.
• Tissue Specificity: Expressed in brain with higher expression in cerebellum, cerebral cortex and amygdala. Expressed in the hematopoietic system. Expressed in T-cells (at protein level). Expressed in NK cells (at protein level) .
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Platelet activation (hsa04611)
  T cell receptor sig.ling pathway (hsa04660)
  Pathways in cancer (hsa05200)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
• Reactome Pathway:
  Activation of RAS in B cells (R-HSA-1169092)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  Integrin signaling (R-HSA-354192)
  Rap1 signalling (R-HSA-392517)
  RAF/MAP kinase cascade (R-HSA-5673001)
  Effects of PIP2 hydrolysis (R-HSA-114508)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Definitive	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[4]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[5]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[5]
Autoimmune lymphoproliferative syndrome type 1	DISAFGRA	Strong	Genetic Variation	[6]
B-cell neoplasm	DISVY326	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[8]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[9]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[5]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[10]
Immunodeficiency	DIS093I0	Strong	Biomarker	[11]
Immunodeficiency 64	DIS58F9B	Strong	Autosomal recessive	[12]
Lymphoma	DISN6V4S	Strong	Biomarker	[4]
Lymphoproliferative syndrome	DISMVL8O	Strong	Genetic Variation	[7]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[4]
Pelvic inflammatory disease	DISWQR4J	Strong	Biomarker	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[15]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[5]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[16]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Altered Expression	[17]
T-cell leukaemia	DISJ6YIF	Strong	Altered Expression	[18]
T-cell lymphoma	DISSXRTQ	Strong	Altered Expression	[18]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[19]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[20]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[21]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[9]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	moderate	Genetic Variation	[14]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[22]
Epidermodysplasia verruciformis	DIS54WBS	moderate	Genetic Variation	[23]
Hashimoto thyroiditis	DIS77CDF	moderate	Genetic Variation	[24]
Inherited bleeding disorder, platelet-type	DISIUNXT	moderate	Biomarker	[25]
Autoimmune lymphoproliferative syndrome	DISUG5ES	Supportive	Autosomal dominant	[6]
Endometriosis	DISX1AG8	Disputed	Biomarker	[26]
Classic Hodgkin lymphoma	DISV1LU6	Limited	Altered Expression	[27]
Epstein barr virus infection	DISOO0WT	Limited	Biomarker	[27]
Microphthalmia	DISGEBES	Limited	Biomarker	[28]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[29]

1 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 RAS guanyl-releasing protein 1 (RASGRP1).	[30]

21 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 RAS guanyl-releasing protein 1 (RASGRP1).	[31]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[32]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[33]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[34]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[35]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[36]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[37]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[38]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[39]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[40]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[41]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[42]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[44]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[45]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[46]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[47]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[48]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[49]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[50]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[51]
Taurine	DMVW7N3	Investigative	Taurine increases the expression of RAS guanyl-releasing protein 1 (RASGRP1).	[52]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of RAS guanyl-releasing protein 1 (RASGRP1).	[43]

References

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