Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUNQ2CT)

• DOT Name: Leucine-rich repeat protein SHOC-2 (SHOC2)
• Synonyms: Protein soc-2 homolog; Protein sur-8 homolog
• Gene Name: SHOC2
• Related Disease:
  Noonan syndrome-like disorder with loose anagen hair
  Noonan syndrome-like disorder with loose anagen hair 1
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Cleft palate
  Colorectal carcinoma
  Hypopituitarism
  Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
  Isolated cleft palate
  Lung cancer
  Lung carcinoma
  Moyamoya disease
  Myelofibrosis
  Non-small-cell lung cancer
  Noonan syndrome 3
  Primary myelofibrosis
  Systemic lupus erythematosus
  Craniosynostosis
  Hydrops fetalis
  Melanoma
  Cardiofaciocutaneous syndrome
  Costello syndrome
  Noonan syndrome
  Skin disease
  Arrhythmia
  Hypertrophic cardiomyopathy
  Intellectual disability
  Noonan syndrome 1
  Noonan syndrome with multiple lentigines
• UniProt ID: SHOC2_HUMAN
• PDB ID: 7SD0; 7SD1; 7T7A; 7TVF; 7TVG; 7TXH; 7TYG; 7UPI
• Pfam ID: PF13855
• Sequence:
  MSSSLGKEKDSKEKDPKVPSAKEREKEAKASGGFGKESKEKEPKTKGKDAKDGKKDSSAA
  QPGVAFSVDNTIKRPNPAPGTRKKSSNAEVIKELNKCREENSMRLDLSKRSIHILPSSIK
  ELTQLTELYLYSNKLQSLPAEVGCLVNLMTLALSENSLTSLPDSLDNLKKLRMLDLRHNK
  LREIPSVVYRLDSLTTLYLRFNRITTVEKDIKNLSKLSMLSIRENKIKQLPAEIGELCNL
  ITLDVAHNQLEHLPKEIGNCTQITNLDLQHNELLDLPDTIGNLSSLSRLGLRYNRLSAIP
  RSLAKCSALEELNLENNNISTLPESLLSSLVKLNSLTLARNCFQLYPVGGPSQFSTIYSL
  NMEHNRINKIPFGIFSRAKVLSKLNMKDNQLTSLPLDFGTWTSMVELNLATNQLTKIPED
  VSGLVSLEVLILSNNLLKKLPHGLGNLRKLRELDLEENKLESLPNEIAYLKDLQKLVLTN
  NQLTTLPRGIGHLTNLTHLGLGENLLTHLPEEIGTLENLEELYLNDNPNLHSLPFELALC
  SKLSIMSIENCPLSHLPPQIVAGGPSFIIQFLKMQGPYRAMV
• Function: Regulatory subunit of protein phosphatase 1 (PP1c) that acts as a M-Ras/MRAS effector and participates in MAPK pathway activation. Upon M-Ras/MRAS activation, targets PP1c to specifically dephosphorylate the 'Ser-259' inhibitory site of RAF1 kinase and stimulate RAF1 activity at specialized signaling complexes.
• KEGG Pathway: Ras sig.ling pathway (hsa04014)
• Reactome Pathway:
  SHOC2 M1731 mutant abolishes MRAS complex function (R-HSA-9726840)
  Gain-of-function MRAS complexes activate RAF signaling (R-HSA-9726842)
  RAF activation (R-HSA-5673000)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Noonan syndrome-like disorder with loose anagen hair	DISWMZIV	Definitive	Autosomal dominant	[1]
Noonan syndrome-like disorder with loose anagen hair 1	DISY66RE	Definitive	Autosomal dominant	[2]
Thyroid cancer	DIS3VLDH	Definitive	Biomarker	[3]
Thyroid gland carcinoma	DISMNGZ0	Definitive	Biomarker	[3]
Thyroid tumor	DISLVKMD	Definitive	Biomarker	[3]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Hypopituitarism	DIS1QT3G	Strong	Genetic Variation	[4]
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia	DISK4S94	Strong	Biomarker	[6]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[4]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[7]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[7]
Moyamoya disease	DISO62CA	Strong	Genetic Variation	[8]
Myelofibrosis	DISIMP21	Strong	Genetic Variation	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Noonan syndrome 3	DIS4MLJP	Strong	CausalMutation	[11]
Primary myelofibrosis	DIS6L0CN	Strong	Genetic Variation	[9]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[12]
Craniosynostosis	DIS6J405	moderate	Genetic Variation	[13]
Hydrops fetalis	DISD9BBF	moderate	Genetic Variation	[14]
Melanoma	DIS1RRCY	moderate	Biomarker	[15]
Cardiofaciocutaneous syndrome	DISZJKSC	Disputed	Autosomal dominant	[1]
Costello syndrome	DISXVJH3	Disputed	Autosomal dominant	[1]
Noonan syndrome	DIS7Q7DN	Disputed	Autosomal dominant	[1]
Skin disease	DISDW8R6	Disputed	Biomarker	[2]
Arrhythmia	DISFF2NI	Limited	Altered Expression	[16]
Hypertrophic cardiomyopathy	DISQG2AI	Limited	Genetic Variation	[17]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[18]
Noonan syndrome 1	DIS7M92N	Limited	Biomarker	[2]
Noonan syndrome with multiple lentigines	DIS014D0	Limited	Genetic Variation	[19]

1 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 Leucine-rich repeat protein SHOC-2 (SHOC2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Leucine-rich repeat protein SHOC-2 (SHOC2).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Leucine-rich repeat protein SHOC-2 (SHOC2).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Leucine-rich repeat protein SHOC-2 (SHOC2).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Leucine-rich repeat protein SHOC-2 (SHOC2).	[24]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Leucine-rich repeat protein SHOC-2 (SHOC2).	[25]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Leucine-rich repeat protein SHOC-2 (SHOC2).	[26]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009 Sep;41(9):1022-6. doi: 10.1038/ng.425. Epub 2009 Aug 16.
• [3] MiR-299-3p functions as a tumor suppressor in thyroid cancer by regulating SHOC2.Eur Rev Med Pharmacol Sci. 2019 Jan;23(1):232-240. doi: 10.26355/eurrev_201901_16769.
• [4] Cleft palate and hypopituitarism in a patient with Noonan-like syndrome with loose anagen hair-1.Am J Med Genet A. 2018 Sep;176(9):2024-2027. doi: 10.1002/ajmg.a.40432. Epub 2018 Sep 21.
• [5] Stabilization of Sur8 via PKC/ degradation promotes transformation and migration of colorectal cancer cells.Oncotarget. 2017 Dec 14;8(70):115596-115608. doi: 10.18632/oncotarget.23313. eCollection 2017 Dec 29.
• [6] VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: novel insights into IBMPFD pathology.Mol Biol Cell. 2019 Jul 1;30(14):1655-1663. doi: 10.1091/mbc.E19-03-0144. Epub 2019 May 15.
• [7] The FBXW7-SHOC2-Raptor Axis Controls the Cross-Talks between the RAS-ERK and mTORC1 Signaling Pathways.Cell Rep. 2019 Mar 12;26(11):3037-3050.e4. doi: 10.1016/j.celrep.2019.02.052.
• [8] Moyamoya disease in two patients with Noonan-like syndrome with loose anagen hair.Am J Med Genet A. 2015 Jun;167(6):1285-8. doi: 10.1002/ajmg.a.37053. Epub 2015 Apr 9.
• [9] Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.Am J Med Genet A. 2013 Oct;161A(10):2420-30. doi: 10.1002/ajmg.a.36098. Epub 2013 Aug 5.
• [10] SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers.Nat Commun. 2019 Jun 10;10(1):2532. doi: 10.1038/s41467-019-10367-x.
• [11] Functional evaluation of circulating hematopoietic progenitors in Noonan syndrome.Oncol Rep. 2013 Aug;30(2):553-9. doi: 10.3892/or.2013.2535. Epub 2013 Jun 11.
• [12] Systemic lupus erythematosus in a patient with Noonan syndrome-like disorder with loose anagen hair 1: More than a chance association.Am J Med Genet A. 2018 Jul;176(7):1662-1666. doi: 10.1002/ajmg.a.38834. Epub 2018 May 7.
• [13] Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype.Am J Med Genet A. 2017 Sep;173(9):2346-2352. doi: 10.1002/ajmg.a.38337. Epub 2017 Jun 26.
• [14] Hydrops fetalis in a preterm newborn heterozygous for the c.4A>G SHOC2 mutation.Am J Med Genet A. 2014 Apr;164A(4):1015-20. doi: 10.1002/ajmg.a.36376. Epub 2014 Jan 23.
• [15] Sur8/Shoc2 promotes cell motility and metastasis through activation of Ras-PI3K signaling.Oncotarget. 2015 Oct 20;6(32):33091-105. doi: 10.18632/oncotarget.5173.
• [16] SUR-8 interacts with PP1-87B to stabilize PERIOD and regulate circadian rhythms in Drosophila.PLoS Genet. 2019 Nov 11;15(11):e1008475. doi: 10.1371/journal.pgen.1008475. eCollection 2019 Nov.
• [17] Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy.Hum Mutat. 2019 Aug;40(8):1046-1056. doi: 10.1002/humu.23767. Epub 2019 May 6.
• [18] Noonan syndrome due to a SHOC2 mutation presenting with fetal distress and fatal hypertrophic cardiomyopathy in a premature infant.Am J Med Genet A. 2012 Jun;158A(6):1411-3. doi: 10.1002/ajmg.a.35318. Epub 2012 Apr 23.
• [19] Spectrum of mutations in Noonan syndrome and their correlation with phenotypes.J Pediatr. 2011 Dec;159(6):1029-35. doi: 10.1016/j.jpeds.2011.05.024. Epub 2011 Jul 23.
• [20] 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.
• [21] 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.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [24] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [25] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [26] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.