Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIXBU8H)

• DOT Name: Polycystin-2 (PKD2)
• Synonyms: PC2; Autosomal dominant polycystic kidney disease type II protein; Polycystic kidney disease 2 protein; Polycystwin; R48321; Transient receptor potential cation channel subfamily P member 2
• Gene Name: PKD2
• Related Disease:
  Autosomal dominant polycystic kidney disease
  Adult glioblastoma
  Advanced cancer
  Atrial fibrillation
  Autism spectrum disorder
  Autosomal dominant polycystic liver disease
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Cholangiocarcinoma
  Chronic kidney disease
  Chronic renal failure
  Colorectal carcinoma
  Congenital contractural arachnodactyly
  Congestive heart failure
  Cystic kidney disease
  Focal segmental glomerulosclerosis
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Hydrocephalus
  Kidney failure
  Laryngeal squamous cell carcinoma
  leukaemia
  Leukemia
  Lung adenocarcinoma
  Neoplasm
  Nephropathy
  Pancreas disorder
  Pheochromocytoma
  Polycystic kidney disease 2
  Polycystic liver disease 1
  Prostate cancer
  Prostate carcinoma
  Renal fibrosis
  Retinopathy
  Triple negative breast cancer
  Vascular disease
  Fetal growth restriction
  Head and neck cancer
  Head and neck carcinoma
  High blood pressure
  Acute kidney injury
  Bladder cancer
  End-stage renal disease
  Familial adenomatous polyposis
  Gout
  Neuroendocrine neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: PKD2_HUMAN
• PDB ID: 2KLD; 2KLE; 2KQ6; 2Y4Q; 3HRN; 3HRO; 5K47; 5MKE; 5MKF; 5T4D; 6A70; 6D1W; 6T9N; 6T9O; 6WB8
• Pfam ID: PF18109 ; PF08016 ; PF20519
• Sequence:
  MVNSSRVQPQQPGDAKRPPAPRAPDPGRLMAGCAAVGASLAAPGGLCEQRGLEIEMQRIR
  QAAARDPPAGAAASPSPPLSSCSRQAWSRDNPGFEAEEEEEEVEGEEGGMVVEMDVEWRP
  GSRRSAASSAVSSVGARSRGLGGYHGAGHPSGRRRRREDQGPPCPSPVGGGDPLHRHLPL
  EGQPPRVAWAERLVRGLRGLWGTRLMEESSTNREKYLKSVLRELVTYLLFLIVLCILTYG
  MMSSNVYYYTRMMSQLFLDTPVSKTEKTNFKTLSSMEDFWKFTEGSLLDGLYWKMQPSNQ
  TEADNRSFIFYENLLLGVPRIRQLRVRNGSCSIPQDLRDEIKECYDVYSVSSEDRAPFGP
  RNGTAWIYTSEKDLNGSSHWGIIATYSGAGYYLDLSRTREETAAQVASLKKNVWLDRGTR
  ATFIDFSVYNANINLFCVVRLLVEFPATGGVIPSWQFQPLKLIRYVTTFDFFLAACEIIF
  CFFIFYYVVEEILEIRIHKLHYFRSFWNCLDVVIVVLSVVAIGINIYRTSNVEVLLQFLE
  DQNTFPNFEHLAYWQIQFNNIAAVTVFFVWIKLFKFINFNRTMSQLSTTMSRCAKDLFGF
  AIMFFIIFLAYAQLAYLVFGTQVDDFSTFQECIFTQFRIILGDINFAEIEEANRVLGPIY
  FTTFVFFMFFILLNMFLAIINDTYSEVKSDLAQQKAEMELSDLIRKGYHKALVKLKLKKN
  TVDDISESLRQGGGKLNFDELRQDLKGKGHTDAEIEAIFTKYDQDGDQELTEHEHQQMRD
  DLEKEREDLDLDHSSLPRPMSSRSFPRSLDDSEEDDDEDSGHSSRRRGSISSGVSYEEFQ
  VLVRRVDRMEHSIGSIVSKIDAVIVKLEIMERAKLKRREVLGRLLDGVAEDERLGRDSEI
  HREQMERLVREELERWESDDAASQISHGLGTPVGLNGQPRPRSSRPSSSQSTEGMEGAGG
  NGSSNVHV
• Function: Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B. Can also form a functional, homotetrameric ion channel. Functions as a cation channel involved in fluid-flow mechanosensation by the primary cilium in renal epithelium. Functions as outward-rectifying K(+) channel, but is also permeable to Ca(2+), and to a much lesser degree also to Na(+). May contribute to the release of Ca(2+) stores from the endoplasmic reticulum. Together with TRPV4, forms mechano- and thermosensitive channels in cilium. PKD1 and PKD2 may function through a common signaling pathway that is necessary to maintain the normal, differentiated state of renal tubule cells. Acts as a regulator of cilium length, together with PKD1. The dynamic control of cilium length is essential in the regulation of mechanotransductive signaling. The cilium length response creates a negative feedback loop whereby fluid shear-mediated deflection of the primary cilium, which decreases intracellular cAMP, leads to cilium shortening and thus decreases flow-induced signaling. Also involved in left-right axis specification via its role in sensing nodal flow; forms a complex with PKD1L1 in cilia to facilitate flow detection in left-right patterning. Detection of asymmetric nodal flow gives rise to a Ca(2+) signal that is required for normal, asymmetric expression of genes involved in the specification of body left-right laterality.
• Tissue Specificity: Detected in fetal and adult kidney . Detected at the thick ascending limb of the loop of Henle, at distal tubules, including the distal convoluted tubule and cortical collecting tubules, with weak staining of the collecting duct . Detected on placenta syncytiotrophoblasts (at protein level) . Strongly expressed in ovary, fetal and adult kidney, testis, and small intestine. Not detected in peripheral leukocytes.
• Reactome Pathway: VxPx cargo-targeting to cilium (R-HSA-5620916)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant polycystic kidney disease	DISBHWUI	Definitive	Autosomal dominant	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[4]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[5]
Autosomal dominant polycystic liver disease	DISJS005	Strong	Genetic Variation	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cardiac failure	DISDC067	Strong	Genetic Variation	[8]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[3]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[9]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[11]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Biomarker	[3]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[8]
Cystic kidney disease	DISRT1LM	Strong	Biomarker	[12]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Biomarker	[13]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[16]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[17]
Laryngeal squamous cell carcinoma	DIS9UUVF	Strong	Biomarker	[18]
leukaemia	DISS7D1V	Strong	Biomarker	[14]
Leukemia	DISNAKFL	Strong	Biomarker	[14]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[19]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[20]
Pancreas disorder	DISDH7NI	Strong	Genetic Variation	[21]
Pheochromocytoma	DIS56IFV	Strong	Altered Expression	[22]
Polycystic kidney disease 2	DIS4UQIF	Strong	Autosomal dominant	[23]
Polycystic liver disease 1	DIS52T2A	Strong	Biomarker	[24]
Prostate cancer	DISF190Y	Strong	Biomarker	[25]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[25]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[26]
Retinopathy	DISB4B0F	Strong	Biomarker	[27]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[28]
Vascular disease	DISVS67S	Strong	Biomarker	[27]
Fetal growth restriction	DIS5WEJ5	moderate	Altered Expression	[29]
Head and neck cancer	DISBPSQZ	moderate	Biomarker	[18]
Head and neck carcinoma	DISOU1DS	moderate	Biomarker	[18]
High blood pressure	DISY2OHH	moderate	Biomarker	[30]
Acute kidney injury	DISXZG0T	Limited	Biomarker	[31]
Bladder cancer	DISUHNM0	Limited	Biomarker	[32]
End-stage renal disease	DISXA7GG	Limited	Genetic Variation	[10]
Familial adenomatous polyposis	DISW53RE	Limited	Altered Expression	[33]
Gout	DISHC0U7	Limited	Genetic Variation	[34]
Neuroendocrine neoplasm	DISNPLOO	Limited	Biomarker	[35]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[32]
Urinary bladder neoplasm	DIS7HACE	Limited	Altered Expression	[32]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Polycystin-2 (PKD2) increases the response to substance of Paclitaxel.	[46]
Capecitabine	DMTS85L	Approved	Polycystin-2 (PKD2) decreases the response to substance of Capecitabine.	[46]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Polycystin-2 (PKD2).	[36]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Polycystin-2 (PKD2).	[37]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Polycystin-2 (PKD2).	[38]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Polycystin-2 (PKD2).	[39]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Polycystin-2 (PKD2).	[40]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Polycystin-2 (PKD2).	[41]
Gentamicin	DMKINJO	Approved	Gentamicin increases the expression of Polycystin-2 (PKD2).	[42]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Polycystin-2 (PKD2).	[43]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Polycystin-2 (PKD2).	[44]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Polycystin-2 (PKD2).	[45]

References

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• [32] Protein kinase D inhibitor CRT0066101 suppresses bladder cancer growth in vitro and xenografts via blockade of the cell cycle at G2/M.Cell Mol Life Sci. 2018 Mar;75(5):939-963. doi: 10.1007/s00018-017-2681-z. Epub 2017 Oct 25.
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