Details of Drug Off-Target (DOT)

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

• DOT Name: Proline-rich protein 5 (PRR5)
• Synonyms: Protein observed with Rictor-1; Protor-1
• Gene Name: PRR5
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Colorectal neoplasm
  Neoplasm
• UniProt ID: PRR5_HUMAN
• Pfam ID: PF08539
• Sequence:
  MRTLRRLKFMSSPSLSDLGKREPAAAADERGTQQRRACANATWNSIHNGVIAVFQRKGLP
  DQELFSLNEGVRQLLKTELGSFFTEYLQNQLLTKGMVILRDKIRFYEGQKLLDSLAETWD
  FFFSDVLPMLQAIFYPVQGKEPSVRQLALLHFRNAITLSVKLEDALARAHARVPPAIVQM
  LLVLQGVHESRGVTEDYLRLETLVQKVVSPYLGTYGLHSSEGPFTHSCILEKRLLRRSRS
  GDVLAKNPVVRSKSYNTPLLNPVQEHEAEGAAAGGTSIRRHSVSEMTSCPEPQGFSDPPG
  QGPTGTFRSSPAPHSGPCPSRLYPTTQPPEQGLDPTRSSLPRSSPENLVDQILESVDSDS
  EGIFIDFGRGRGSGMSDLEGSGGRQSVV
• Function: Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. PRR5 plays an important role in regulation of PDGFRB expression and in modulation of platelet-derived growth factor signaling. May act as a tumor suppressor in breast cancer.
• Tissue Specificity: Most abundant in kidney and liver. Also highly expressed in brain, spleen, testis and placenta. Overexpressed in several colorectal tumors.
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway:
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  Regulation of TP53 Degradation (R-HSA-6804757)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[1]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]

4 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 Proline-rich protein 5 (PRR5).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Proline-rich protein 5 (PRR5).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Proline-rich protein 5 (PRR5).	[7]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Proline-rich protein 5 (PRR5).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Proline-rich protein 5 (PRR5).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Proline-rich protein 5 (PRR5).	[4]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Proline-rich protein 5 (PRR5).	[5]

References

• [1] PRR5 encodes a conserved proline-rich protein predominant in kidney: analysis of genomic organization, expression, and mutation status in breast and colorectal carcinomas.Genomics. 2005 Mar;85(3):338-51. doi: 10.1016/j.ygeno.2004.11.002.
• [2] 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.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] 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.
• [5] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [6] 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.
• [7] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.