Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTETYX40)

• DOT Name: Proto-oncogene tyrosine-protein kinase Src (SRC)
• Synonyms: EC 2.7.10.2; Proto-oncogene c-Src; pp60c-src; p60-Src
• Gene Name: SRC
• Related Disease:
  Thrombocytopenia 6
  Colorectal cancer
• UniProt ID: SRC_HUMAN
• PDB ID: 1A07 ; 1A08 ; 1A09 ; 1A1A ; 1A1B ; 1A1C ; 1A1E ; 1FMK ; 1HCS ; 1HCT ; 1KSW ; 1O41 ; 1O42 ; 1O43 ; 1O44 ; 1O45 ; 1O46 ; 1O47 ; 1O48 ; 1O49 ; 1O4A ; 1O4B ; 1O4C ; 1O4D ; 1O4E ; 1O4F ; 1O4G ; 1O4H ; 1O4I ; 1O4J ; 1O4K ; 1O4L ; 1O4M ; 1O4N ; 1O4O ; 1O4P ; 1O4Q ; 1O4R ; 1SHD ; 1Y57 ; 1YI6 ; 1YOJ ; 1YOL ; 1YOM ; 2BDF ; 2BDJ ; 2H8H ; 2SRC ; 3VRO ; 3ZMP ; 3ZMQ ; 4F59 ; 4F5A ; 4F5B ; 4HXJ ; 4K11 ; 4MXO ; 4MXX ; 4MXY ; 4MXZ ; 6ATE ; 6C4S ; 6E6E ; 6EHJ ; 7NG7 ; 7OTE ; 7T1U ; 7YQE ; 8HAQ
• EC Number: 2.7.10.2
• Pfam ID: PF07714 ; PF00017 ; PF00018
• Sequence:
  MGSNKSKPKDASQRRRSLEPAENVHGAGGGAFPASQTPSKPASADGHRGPSAAFAPAAAE
  PKLFGGFNSSDTVTSPQRAGPLAGGVTTFVALYDYESRTETDLSFKKGERLQIVNNTEGD
  WWLAHSLSTGQTGYIPSNYVAPSDSIQAEEWYFGKITRRESERLLLNAENPRGTFLVRES
  ETTKGAYCLSVSDFDNAKGLNVKHYKIRKLDSGGFYITSRTQFNSLQQLVAYYSKHADGL
  CHRLTTVCPTSKPQTQGLAKDAWEIPRESLRLEVKLGQGCFGEVWMGTWNGTTRVAIKTL
  KPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEEPIYIVTEYMSKGSLLDFLKGETGKY
  LRLPQLVDMAAQIASGMAYVERMNYVHRDLRAANILVGENLVCKVADFGLARLIEDNEYT
  ARQGAKFPIKWTAPEAALYGRFTIKSDVWSFGILLTELTTKGRVPYPGMVNREVLDQVER
  GYRMPCPPECPESLHDLMCQCWRKEPEERPTFEYLQAFLEDYFTSTEPQYQPGENL
• Function: Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN) (Probable). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin-43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1 (Probable). Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors. Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1. Plays a role in EGF-mediated calcium-activated chloride channel activation. Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr-1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of GRK2, leading to beta-arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor (Probable). Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus. Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase. Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation. Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-731'. Enhances RIGI-elicited antiviral signaling. Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376'. Phosphorylates BCAR1 at 'Tyr-128'. Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity. Phosphorylates synaptic vesicle protein synaptophysin (SYP). Involved in anchorage-independent cell growth. Required for podosome formation. Mediates IL6 signaling by activating YAP1-NOTCH pathway to induce inflammation-induced epithelial regeneration. Phosphorylates OTUB1, promoting deubiquitination of RPTOR. Phosphorylates caspase CASP8 at 'Tyr-380' which negatively regulates CASP8 processing and activation, down-regulating CASP8 proapoptotic function ; [Isoform 1]: Non-receptor protein tyrosine kinase which phosphorylates synaptophysin with high affinity; [Isoform 2]: Non-receptor protein tyrosine kinase which shows higher basal kinase activity than isoform 1, possibly due to weakened intramolecular interactions which enhance autophosphorylation of Tyr-419 and subsequent activation. The SH3 domain shows reduced affinity with the linker sequence between the SH2 and kinase domains which may account for the increased basal activity. Displays altered substrate specificity compared to isoform 1, showing weak affinity for synaptophysin and for peptide substrates containing class I or class II SH3 domain-binding motifs. Plays a role in L1CAM-mediated neurite elongation, possibly by acting downstream of L1CAM to drive cytoskeletal rearrangements involved in neurite outgrowth; [Isoform 3]: Non-receptor protein tyrosine kinase which shows higher basal kinase activity than isoform 1, possibly due to weakened intramolecular interactions which enhance autophosphorylation of Tyr-419 and subsequent activation. The SH3 domain shows reduced affinity with the linker sequence between the SH2 and kinase domains which may account for the increased basal activity. Displays altered substrate specificity compared to isoform 1, showing weak affinity for synaptophysin and for peptide substrates containing class I or class II SH3 domain-binding motifs. Plays a role in neurite elongation.
• Tissue Specificity: Expressed ubiquitously. Platelets, neurons and osteoclasts express 5-fold to 200-fold higher levels than most other tissues.; [Isoform 1]: Expressed in spleen and liver.; [Isoform 2]: Expressed in brain.; [Isoform 3]: Expressed in brain.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  Endocrine resistance (hsa01522)
  ErbB sig.ling pathway (hsa04012)
  Rap1 sig.ling pathway (hsa04015)
  Chemokine sig.ling pathway (hsa04062)
  Mitophagy - animal (hsa04137)
  Endocytosis (hsa04144)
  Axon guidance (hsa04360)
  VEGF sig.ling pathway (hsa04370)
  Focal adhesion (hsa04510)
  Adherens junction (hsa04520)
  Tight junction (hsa04530)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  Neutrophil extracellular trap formation (hsa04613)
  C-type lectin receptor sig.ling pathway (hsa04625)
  GABAergic sy.pse (hsa04727)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Regulation of actin cytoskeleton (hsa04810)
  GnRH sig.ling pathway (hsa04912)
  Estrogen sig.ling pathway (hsa04915)
  Prolactin sig.ling pathway (hsa04917)
  Thyroid hormone sig.ling pathway (hsa04919)
  Oxytocin sig.ling pathway (hsa04921)
  Relaxin sig.ling pathway (hsa04926)
  Bacterial invasion of epithelial cells (hsa05100)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Yersinia infection (hsa05135)
  Tuberculosis (hsa05152)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Viral carcinogenesis (hsa05203)
  Proteoglycans in cancer (hsa05205)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Bladder cancer (hsa05219)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Nuclear signaling by ERBB4 (R-HSA-1251985)
  Downregulation of ERBB4 signaling (R-HSA-1253288)
  PIP3 activates AKT signaling (R-HSA-1257604)
  GAB1 signalosome (R-HSA-180292)
  Downstream signal transduction (R-HSA-186763)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  Integrin signaling (R-HSA-354192)
  GRB2 (R-HSA-354194)
  p130Cas linkage to MAPK signaling for integrins (R-HSA-372708)
  G alpha (s) signalling events (R-HSA-418555)
  G alpha (i) signalling events (R-HSA-418594)
  DCC mediated attractive signaling (R-HSA-418885)
  Netrin mediated repulsion signals (R-HSA-418886)
  Regulation of commissural axon pathfinding by SLIT and ROBO (R-HSA-428542)
  RAF activation (R-HSA-5673000)
  MAP2K and MAPK activation (R-HSA-5674135)
  Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946)
  Signaling by high-kinase activity BRAF mutants (R-HSA-6802948)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  MET activates PTK2 signaling (R-HSA-8874081)
  InlA-mediated entry of Listeria monocytogenes into host cells (R-HSA-8876493)
  Regulation of RUNX1 Expression and Activity (R-HSA-8934593)
  RUNX2 regulates osteoblast differentiation (R-HSA-8940973)
  Regulation of RUNX3 expression and activity (R-HSA-8941858)
  Extra-nuclear estrogen signaling (R-HSA-9009391)
  RHOU GTPase cycle (R-HSA-9013420)
  Activated NTRK2 signals through FYN (R-HSA-9032500)
  Activated NTRK3 signals through PI3K (R-HSA-9603381)
  Long-term potentiation (R-HSA-9620244)
  GPER1 signaling (R-HSA-9634597)
  Signaling downstream of RAS mutants (R-HSA-9649948)
  Signaling by RAF1 mutants (R-HSA-9656223)
  Signaling by CSF1 (M-CSF) in myeloid cells (R-HSA-9680350)
  Signaling by ERBB2 (R-HSA-1227986)
• BioCyc Pathway: MetaCyc:HS02256-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thrombocytopenia 6	DISBCBHB	Moderate	Autosomal dominant	[1]
Colorectal cancer	DISNH7P9	No Known	Unknown	[2]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Proto-oncogene tyrosine-protein kinase Src (SRC) decreases the response to substance of Cisplatin.	[53]
Gemcitabine	DMSE3I7	Approved	Proto-oncogene tyrosine-protein kinase Src (SRC) decreases the response to substance of Gemcitabine.	[54]
Carvedilol	DMHTEAO	Approved	Proto-oncogene tyrosine-protein kinase Src (SRC) increases the Vascular disorders ADR of Carvedilol.	[55]

26 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 Proto-oncogene tyrosine-protein kinase Src (SRC).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[15]
Nicotine	DMWX5CO	Approved	Nicotine increases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[17]
Ritonavir	DMU764S	Approved	Ritonavir decreases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[20]
Prasterone	DM67VKL	Approved	Prasterone increases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[22]
Bosutinib	DMTI8YE	Approved	Bosutinib decreases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[24]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[26]
Buparlisib	DM1WEHC	Phase 3	Buparlisib increases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[28]
Thymoquinone	DMVDTR2	Phase 2/3	Thymoquinone decreases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[29]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[30]
XL880	DMHJTR2	Phase 2	XL880 decreases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[32]
G1	DMTV42K	Phase 1/2	G1 increases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[34]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[36]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[38]
AG490	DM3WKO5	Terminated	AG490 decreases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[39]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[42]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[44]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl affects the methylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[46]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[47]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[48]
Fmet-leu-phe	DMQ391A	Investigative	Fmet-leu-phe increases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[49]
[3H]CP55940	DMU7FC5	Investigative	[3H]CP55940 increases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[50]
CGP 77675	DMXH2R3	Investigative	CGP 77675 decreases the phosphorylation of Proto-oncogene tyrosine-protein kinase Src (SRC).	[52]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the activity of Proto-oncogene tyrosine-protein kinase Src (SRC).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the activity of Proto-oncogene tyrosine-protein kinase Src (SRC).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[14]
Folic acid	DMEMBJC	Approved	Folic acid increases the activity of Proto-oncogene tyrosine-protein kinase Src (SRC).	[16]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[13]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the activity of Proto-oncogene tyrosine-protein kinase Src (SRC).	[18]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[19]
Propofol	DMB4OLE	Approved	Propofol increases the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[21]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[21]
Plicamycin	DM7C8YV	Approved	Plicamycin decreases the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[23]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the activity of Proto-oncogene tyrosine-protein kinase Src (SRC).	[25]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the activity of Proto-oncogene tyrosine-protein kinase Src (SRC).	[27]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[35]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Proto-oncogene tyrosine-protein kinase Src (SRC).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[40]
Deguelin	DMXT7WG	Investigative	Deguelin increases the activity of Proto-oncogene tyrosine-protein kinase Src (SRC).	[41]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[43]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Proto-oncogene tyrosine-protein kinase Src (SRC).	[45]
Benzamidine	DM37GWL	Investigative	Benzamidine decreases the activity of Proto-oncogene tyrosine-protein kinase Src (SRC).	[51]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN affects the binding of Proto-oncogene tyrosine-protein kinase Src (SRC).	[31]

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