Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT305NPA)

DOT Name SHC-transforming protein 3 (SHC3)
Synonyms Neuronal Shc; N-Shc; Protein Rai; SHC-transforming protein C; Src homology 2 domain-containing-transforming protein C3; SH2 domain protein C3
Gene Name SHC3
Related Disease
Adult glioblastoma ( )
Differentiated thyroid carcinoma ( )
Ependymoma ( )
Glioblastoma multiforme ( )
Non-insulin dependent diabetes ( )
Adenoma ( )
Advanced cancer ( )
Breast cancer ( )
Breast carcinoma ( )
Carcinoma ( )
Colorectal adenoma ( )
Epileptic encephalopathy ( )
Graves disease ( )
Hairy cell leukaemia ( )
Lung cancer ( )
Lung carcinoma ( )
Medullary thyroid gland carcinoma ( )
Neoplasm ( )
Nicotine dependence ( )
Plasma cell myeloma ( )
Small lymphocytic lymphoma ( )
Smith-Magenis syndrome ( )
Testicular cancer ( )
X-linked Opitz G/BBB syndrome ( )
Metastatic malignant neoplasm ( )
Thyroid gland papillary carcinoma ( )
Thyrotoxicosis ( )
Cerebral infarction ( )
Right atrial isomerism ( )
Astrocytoma ( )
Glioma ( )
Helicoid peripapillary chorioretinal degeneration ( )
Hepatocellular carcinoma ( )
Parkinson disease ( )
Thyroid gland undifferentiated (anaplastic) carcinoma ( )
UniProt ID
SHC3_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
Pfam ID
PF00640 ; PF00017
Sequence
MLPRTKYNRFRNDSVTSVDDLLHSLSVSGGGGKVSAARATPAAAPYLVSGEALRKAPDDG
PGSLGHLLHKVSHLKLSSSGLRGLSSAARERAGARLSGSCSAPSLAAPDGSAPSAPRAPA
MSAARKGRPGDEPLPRPPRGAPHASDQVLGPGVTYVVKYLGCIEVLRSMRSLDFSTRTQI
TREAISRVCEAVPGAKGAFKKRKPPSKMLSSILGKSNLQFAGMSISLTISTASLNLRTPD
SKQIIANHHMRSISFASGGDPDTTDYVAYVAKDPVNRRACHILECCDGLAQDVIGSIGQA
FELRFKQYLQCPTKIPALHDRMQSLDEPWTEEEGDGSDHPYYNSIPSKMPPPGGFLDTRL
KPRPHAPDTAQFAGKEQTYYQGRHLGDTFGEDWQQTPLRQGSSDIYSTPEGKLHVAPTGE
APTYVNTQQIPPQAWPAAVSSAESSPRKDLFDMKPFEDALKNQPLGPVLSKAASVECISP
VSPRAPDAKMLEELQAETWYQGEMSRKEAEGLLEKDGDFLVRKSTTNPGSFVLTGMHNGQ
AKHLLLVDPEGTIRTKDRVFDSISHLINHHLESSLPIVSAGSELCLQQPVERKQ
Function
Signaling adapter that couples activated growth factor receptors to signaling pathway in neurons. Involved in the signal transduction pathways of neurotrophin-activated Trk receptors in cortical neurons.
Tissue Specificity
Mainly expressed in brain. Hardly detectable in other tissues, except in pancreas. Highly expressed in the cerebral cortex, frontal and temporal lobes, occipital pole, hippocampus, caudate nucleus and amygdala. Expressed at low level in the cerebellum, medulla and spinal cord.
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 )
Glioma (hsa05214 )
Chronic myeloid leukemia (hsa05220 )
Breast cancer (hsa05224 )
Hepatocellular carcinoma (hsa05225 )
Gastric cancer (hsa05226 )
Reactome Pathway
RAF/MAP kinase cascade (R-HSA-5673001 )
RET signaling (R-HSA-8853659 )
Signalling to RAS (R-HSA-167044 )

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Adult glioblastoma DISVP4LU Definitive Altered Expression [1]
Differentiated thyroid carcinoma DIS1V20Y Definitive Biomarker [2]
Ependymoma DISUMRNZ Definitive Biomarker [3]
Glioblastoma multiforme DISK8246 Definitive Altered Expression [1]
Non-insulin dependent diabetes DISK1O5Z Definitive Biomarker [4]
Adenoma DIS78ZEV Strong Genetic Variation [5]
Advanced cancer DISAT1Z9 Strong Biomarker [6]
Breast cancer DIS7DPX1 Strong Genetic Variation [7]
Breast carcinoma DIS2UE88 Strong Genetic Variation [7]
Carcinoma DISH9F1N Strong Genetic Variation [5]
Colorectal adenoma DISTSVHM Strong Biomarker [5]
Epileptic encephalopathy DISZOCA3 Strong Biomarker [8]
Graves disease DISU4KOQ Strong Biomarker [9]
Hairy cell leukaemia DISTD2E5 Strong Biomarker [10]
Lung cancer DISCM4YA Strong Genetic Variation [7]
Lung carcinoma DISTR26C Strong Genetic Variation [7]
Medullary thyroid gland carcinoma DISHBL3K Strong Genetic Variation [11]
Neoplasm DISZKGEW Strong Genetic Variation [12]
Nicotine dependence DISZD9W7 Strong Biomarker [13]
Plasma cell myeloma DIS0DFZ0 Strong Genetic Variation [14]
Small lymphocytic lymphoma DIS30POX Strong Altered Expression [15]
Smith-Magenis syndrome DISG4G6X Strong Genetic Variation [16]
Testicular cancer DIS6HNYO Strong Genetic Variation [17]
X-linked Opitz G/BBB syndrome DISQ14EC Strong Biomarker [8]
Metastatic malignant neoplasm DIS86UK6 moderate Biomarker [2]
Thyroid gland papillary carcinoma DIS48YMM moderate Biomarker [18]
Thyrotoxicosis DISWH7BV moderate Biomarker [19]
Cerebral infarction DISR1WNP Disputed Biomarker [20]
Right atrial isomerism DIS2SZ2Q Disputed Altered Expression [20]
Astrocytoma DISL3V18 Limited Biomarker [21]
Glioma DIS5RPEH Limited Altered Expression [21]
Helicoid peripapillary chorioretinal degeneration DISFSS5N Limited Biomarker [12]
Hepatocellular carcinoma DIS0J828 Limited Biomarker [6]
Parkinson disease DISQVHKL Limited Altered Expression [8]
Thyroid gland undifferentiated (anaplastic) carcinoma DISYBB1W Limited Genetic Variation [22]
------------------------------------------------------------------------------------
⏷ Show the Full List of 35 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
10 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the expression of SHC-transforming protein 3 (SHC3). [23]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of SHC-transforming protein 3 (SHC3). [24]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of SHC-transforming protein 3 (SHC3). [25]
Temozolomide DMKECZD Approved Temozolomide decreases the expression of SHC-transforming protein 3 (SHC3). [26]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of SHC-transforming protein 3 (SHC3). [27]
Dexamethasone DMMWZET Approved Dexamethasone increases the expression of SHC-transforming protein 3 (SHC3). [28]
Acocantherin DM7JT24 Approved Acocantherin increases the expression of SHC-transforming protein 3 (SHC3). [29]
SNDX-275 DMH7W9X Phase 3 SNDX-275 decreases the expression of SHC-transforming protein 3 (SHC3). [30]
Genistein DM0JETC Phase 2/3 Genistein decreases the expression of SHC-transforming protein 3 (SHC3). [31]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of SHC-transforming protein 3 (SHC3). [33]
------------------------------------------------------------------------------------
⏷ Show the Full List of 10 Drug(s)
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of SHC-transforming protein 3 (SHC3). [32]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of SHC-transforming protein 3 (SHC3). [34]
------------------------------------------------------------------------------------

References

1 Cell density modulates SHC3 expression and survival of human glioblastoma cells through Fak activation.J Neurooncol. 2014 Nov;120(2):245-56. doi: 10.1007/s11060-014-1551-x. Epub 2014 Jul 26.
2 LONG-TERM OUTCOMES AND PROGNOSTIC FACTORS IN PATIENTS WITH DIFFERENTIATED THYROID CARCINOMA AND BONE METASTASES.Endocr Pract. 2019 May;25(5):427-437. doi: 10.4158/EP-2018-0465. Epub 2019 Jan 18.
3 EDG3 and SHC3 on chromosome 9q22 are co-amplified in human ependymomas.Cancer Lett. 2010 Apr 1;290(1):36-42. doi: 10.1016/j.canlet.2009.08.023. Epub 2009 Sep 12.
4 Predictors and Clinical Outcomes of Treatment Intensification in Patients With Type 2 Diabetes Uncontrolled on Basal Insulin in a Real-World Setting.Endocr Pract. 2018 Sep;24(9):805-814. doi: 10.4158/EP-2017-0261. Epub 2018 Jul 5.
5 Effects of polymorphisms in ERCC1, ASE-1 and RAI on the risk of colorectal carcinomas and adenomas: a case control study.BMC Cancer. 2006 Jul 3;6:175. doi: 10.1186/1471-2407-6-175.
6 Demethylation-Induced Overexpression of Shc3 Drives c-Raf-Independent Activation of MEK/ERK in HCC.Cancer Res. 2018 May 1;78(9):2219-2232. doi: 10.1158/0008-5472.CAN-17-2432. Epub 2018 Jan 12.
7 A haplotype of polymorphisms in ASE-1, RAI and ERCC1 and the effects of tobacco smoking and alcohol consumption on risk of colorectal cancer: a Danish prospective case-cohort study.BMC Cancer. 2008 Feb 20;8:54. doi: 10.1186/1471-2407-8-54.
8 Lentiviral Vector-Mediated SHC3 Silencing Exacerbates Oxidative Stress Injury in Nigral Dopamine Neurons by Regulating the PI3K-AKT-FoxO Signaling Pathway in Rats with Parkinson's Disease.Cell Physiol Biochem. 2018;49(3):971-984. doi: 10.1159/000493228. Epub 2018 Sep 5.
9 Alemtuzumab-induced thyroid events in multiple sclerosis: a systematic review and meta-analysis.J Endocrinol Invest. 2020 Feb;43(2):219-229. doi: 10.1007/s40618-019-01105-7. Epub 2019 Aug 26.
10 Expression of CD45 isoforms in chronic B-cell leukaemias.Leuk Res. 1993 Mar;17(3):209-16. doi: 10.1016/0145-2126(93)90003-4.
11 Primary Adrenal Insufficiency During Lenvatinib or Vandetanib and Improvement of Fatigue After Cortisone Acetate Therapy.J Clin Endocrinol Metab. 2019 Mar 1;104(3):779-784. doi: 10.1210/jc.2018-01836.
12 Risk Haplotypes Uniquely Associated with Radioiodine-Refractory Thyroid Cancer Patients of High African Ancestry.Thyroid. 2019 Apr;29(4):530-539. doi: 10.1089/thy.2018.0687. Epub 2019 Feb 13.
13 Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence.Mol Psychiatry. 2007 May;12(5):462-73. doi: 10.1038/sj.mp.4001933. Epub 2006 Dec 19.
14 The importance of a sub-region on chromosome 19q13.3 for prognosis of multiple myeloma patients after high-dose treatment and stem cell support: a linkage disequilibrium mapping in RAI and CD3EAP.Ann Hematol. 2011 Jun;90(6):675-84. doi: 10.1007/s00277-010-1105-z. Epub 2010 Nov 3.
15 CD11c expression in chronic lymphocytic leukemia revisited, related with complications and survival.Int J Lab Hematol. 2017 Oct;39(5):552-556. doi: 10.1111/ijlh.12695. Epub 2017 Jun 12.
16 First evidence of Smith-Magenis syndrome in mother and daughter due to a novel RAI mutation.Am J Med Genet A. 2017 Jan;173(1):231-238. doi: 10.1002/ajmg.a.37989. Epub 2016 Sep 28.
17 Polymorphisms in RAI and in genes of nucleotide and base excision repair are not associated with risk of testicular cancer.Cancer Lett. 2005 Jul 28;225(2):245-51. doi: 10.1016/j.canlet.2005.03.021.
18 BRAF V600E and Retinoic Acid in Radioiodine-Refractory Papillary Thyroid Cancer.Horm Metab Res. 2019 Jan;51(1):69-75. doi: 10.1055/a-0765-9078. Epub 2018 Nov 5.
19 Thyroid cancer post radioactive iodine treatment for hyperthyroidism - case series and review of the literature.Endokrynol Pol. 2017;68(5):561-566. doi: 10.5603/EP.a2017.0037. Epub 2017 Jun 6.
20 The Shc protein RAI promotes an adaptive cell survival program in hypoxic neuroblastoma cells.J Cell Physiol. 2018 May;233(5):4282-4293. doi: 10.1002/jcp.26247. Epub 2017 Nov 24.
21 Shc3 affects human high-grade astrocytomas survival.Oncogene. 2005 Aug 4;24(33):5198-206. doi: 10.1038/sj.onc.1208708.
22 Targeted Therapy in Thyroid Cancer: State of the Art.Clin Oncol (R Coll Radiol). 2017 May;29(5):316-324. doi: 10.1016/j.clon.2017.02.009. Epub 2017 Mar 17.
23 Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
24 Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
25 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
26 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.
27 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
28 Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
29 Ouabain impairs cell migration, and invasion and alters gene expression of human osteosarcoma U-2 OS cells. Environ Toxicol. 2017 Nov;32(11):2400-2413. doi: 10.1002/tox.22453. Epub 2017 Aug 10.
30 A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
31 A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
32 Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
33 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.
34 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.