Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ0H76H)

• DOT Name: SHC-transforming protein 4 (SHC4)
• Synonyms: Rai-like protein; RaLP; SHC-transforming protein D; hShcD; Src homology 2 domain-containing-transforming protein C4; SH2 domain protein C4
• Gene Name: SHC4
• Related Disease:
  Narcolepsy
  Bipolar disorder
  Depression
  Melanoma
  Neoplasm
• UniProt ID: SHC4_HUMAN
• Pfam ID: PF00640 ; PF00017
• Sequence:
  MRERGQDSLAGLVLYVGLFGHPGMLHRAKYSRFRNESITSLDEGSSGGSVGNKGSPQPPH
  PALAPHLPTEDATLPSQESPTPLCTLIPRMASMKLANPATLLSLKNFCLGTKEVPRLKLQ
  ESRDPGSSGPSSPETSLSRSGTAPPPQQDLVGHRATALTPDSCPLPGPGEPTLRSRQDRH
  FLQHLLGMGMNYCVRYMGCVEVLQSMRSLDFGMRTQVTREAISRLCEAVPGANGAIKKRK
  PPVKFLSTVLGKSNLQFSGMNIKLTISTCSLTLMNLDNQQIIANHHMQSISFASGGDPDT
  TDYVAYVAKDPVNQRACHILECHNGMAQDVISTIGQAFELRFKQYLKNPSLNTSCESEEV
  HIDSHAEEREDHEYYNEIPGKQPPVGGVSDMRIKVQATEQMAYCPIQCEKLCYLPGNSKC
  SSVYENCLEQSRAIGNVHPRGVQSQRDTSLLKHTCRVDLFDDPCYINTQALQSTPGSAGN
  QRSAQPLGSPWHCGKAPETVQPGATAQPASSHSLPHIKQQLWSEECYHGKLSRKAAESLL
  VKDGDFLVRESATSPGQYVLSGLQGGQAKHLLLVDPEGKVRTKDHVFDNVGHLIRYHMDN
  SLPIISSGSEVSLKQPVRKDNNPALLHSNK
• Function: Activates both Ras-dependent and Ras-independent migratory pathways in melanomas. Contributes to the early phases of agrin-induced tyrosine phosphorylation of CHRNB1.
• Tissue Specificity: Only expressed in melanomas. Weakly expressed in normal melanocytes and benign nevi. Highly expressed at the transition from radial growth phase to vertical growth phase and metastatic melanomas, when tumor cells acquire migratory competence and invasive potential.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  Endocrine resistance (hsa01522)
  ErbB sig.ling pathway (hsa04012)
  Ras sig.ling pathway (hsa04014)
  Chemokine sig.ling pathway (hsa04062)
  Phospholipase D sig.ling pathway (hsa04072)
  Focal adhesion (hsa04510)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Neurotrophin sig.ling pathway (hsa04722)
  Insulin sig.ling pathway (hsa04910)
  Estrogen sig.ling pathway (hsa04915)
  Prolactin sig.ling pathway (hsa04917)
  Relaxin sig.ling pathway (hsa04926)
  Growth hormone synthesis, secretion and action (hsa04935)
  Alcoholism (hsa05034)
  Bacterial invasion of epithelial cells (hsa05100)
  MicroR.s in cancer (hsa05206)
  Glioma (hsa05214)
  Chronic myeloid leukemia (hsa05220)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[1]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[2]
Depression	DIS3XJ69	Strong	Biomarker	[2]
Melanoma	DIS1RRCY	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]

2 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 SHC-transforming protein 4 (SHC4).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of SHC-transforming protein 4 (SHC4).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of SHC-transforming protein 4 (SHC4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of SHC-transforming protein 4 (SHC4).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of SHC-transforming protein 4 (SHC4).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of SHC-transforming protein 4 (SHC4).	[9]
Lucanthone	DMZLBUO	Approved	Lucanthone increases the expression of SHC-transforming protein 4 (SHC4).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of SHC-transforming protein 4 (SHC4).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of SHC-transforming protein 4 (SHC4).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of SHC-transforming protein 4 (SHC4).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of SHC-transforming protein 4 (SHC4).	[15]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of SHC-transforming protein 4 (SHC4).	[16]

References

• [1] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [2] Genetic basis of psychopathological dimensions shared between schizophrenia and bipolar disorder.Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 8;89:23-29. doi: 10.1016/j.pnpbp.2018.08.023. Epub 2018 Aug 24.
• [3] RaLP, a new member of the Src homology and collagen family, regulates cell migration and tumor growth of metastatic melanomas.Cancer Res. 2007 Apr 1;67(7):3064-73. doi: 10.1158/0008-5472.CAN-06-2301.
• [4] Positive surgical margins and early oncological outcomes of robotic vs open radical prostatectomy at a medium case-load institution.Minerva Urol Nefrol. 2017 Feb;69(1):63-68. doi: 10.23736/S0393-2249.16.02518-2. Epub 2016 Mar 9.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [11] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [12] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [13] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.