Details of Drug Off-Target (DOT)

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

• DOT Name: Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1)
• Synonyms: EC 3.1.3.86; Inositol polyphosphate phosphatase-like protein 1; INPPL-1; Protein 51C; SH2 domain-containing inositol 5'-phosphatase 2; SH2 domain-containing inositol phosphatase 2; SHIP-2
• Gene Name: INPPL1
• Related Disease:
  Gastric neoplasm
  Hepatitis B virus infection
  Opsismodysplasia
  Thyroid gland papillary carcinoma
  Acute erythroid leukemia
  Adult glioblastoma
  Alzheimer disease
  Atrial fibrillation
  Bone disease
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Colorectal carcinoma
  Depression
  Diabetic kidney disease
  Essential hypertension
  Gastric cancer
  Glioblastoma multiforme
  Gonorrhea
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Insulinoma
  Metabolic disorder
  Neoplasm
  Nervous system disease
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Obesity
  Osteoporosis-pseudoglioma syndrome
  Plasma cell myeloma
  Stomach cancer
  Turner syndrome
  Type-1/2 diabetes
  Breast cancer
  Breast carcinoma
  Laryngeal squamous cell carcinoma
  Stroke
  Schneckenbecken dysplasia
  Advanced cancer
  High blood pressure
  Small lymphocytic lymphoma
  Type-1 diabetes
• UniProt ID: SHIP2_HUMAN
• PDB ID: 2K4P; 2KSO; 2MK2; 3NR8; 4A9C; 5OKM; 5OKN; 5OKO; 5OKP; 6SQU; 6SRR
• EC Number: 3.1.3.86
• Pfam ID: PF00536 ; PF00017
• Sequence:
  MASACGAPGPGGALGSQAPSWYHRDLSRAAAEELLARAGRDGSFLVRDSESVAGAFALCV
  LYQKHVHTYRILPDGEDFLAVQTSQGVPVRRFQTLGELIGLYAQPNQGLVCALLLPVEGE
  REPDPPDDRDASDGEDEKPPLPPRSGSTSISAPTGPSSPLPAPETPTAPAAESAPNGLST
  VSHDYLKGSYGLDLEAVRGGASHLPHLTRTLATSCRRLHSEVDKVLSGLEILSKVFDQQS
  SPMVTRLLQQQNLPQTGEQELESLVLKLSVLKDFLSGIQKKALKALQDMSSTAPPAPQPS
  TRKAKTIPVQAFEVKLDVTLGDLTKIGKSQKFTLSVDVEGGRLVLLRRQRDSQEDWTTFT
  HDRIRQLIKSQRVQNKLGVVFEKEKDRTQRKDFIFVSARKREAFCQLLQLMKNKHSKQDE
  PDMISVFIGTWNMGSVPPPKNVTSWFTSKGLGKTLDEVTVTIPHDIYVFGTQENSVGDRE
  WLDLLRGGLKELTDLDYRPIAMQSLWNIKVAVLVKPEHENRISHVSTSSVKTGIANTLGN
  KGAVGVSFMFNGTSFGFVNCHLTSGNEKTARRNQNYLDILRLLSLGDRQLNAFDISLRFT
  HLFWFGDLNYRLDMDIQEILNYISRKEFEPLLRVDQLNLEREKHKVFLRFSEEEISFPPT
  YRYERGSRDTYAWHKQKPTGVRTNVPSWCDRILWKSYPETHIICNSYGCTDDIVTSDHSP
  VFGTFEVGVTSQFISKKGLSKTSDQAYIEFESIEAIVKTASRTKFFIEFYSTCLEEYKKS
  FENDAQSSDNINFLKVQWSSRQLPTLKPILADIEYLQDQHLLLTVKSMDGYESYGECVVA
  LKSMIGSTAQQFLTFLSHRGEETGNIRGSMKVRVPTERLGTRERLYEWISIDKDEAGAKS
  KAPSVSRGSQEPRSGSRKPAFTEASCPLSRLFEEPEKPPPTGRPPAPPRAAPREEPLTPR
  LKPEGAPEPEGVAAPPPKNSFNNPAYYVLEGVPHQLLPPEPPSPARAPVPSATKNKVAIT
  VPAPQLGHHRHPRVGEGSSSDEESGGTLPPPDFPPPPLPDSAIFLPPSLDPLPGPVVRGR
  GGAEARGPPPPKAHPRPPLPPGPSPASTFLGEVASGDDRSCSVLQMAKTLSEVDYAPAGP
  ARSALLPGPLELQPPRGLPSDYGRPLSFPPPRIRESIQEDLAEEAPCLQGGRASGLGEAG
  MSAWLRAIGLERYEEGLVHNGWDDLEFLSDITEEDLEEAGVQDPAHKRLLLDTLQLSK
• Function: Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. Required for correct mitotic spindle orientation and therefore progression of mitosis. Plays a central role in regulation of PI3K-dependent insulin signaling, although the precise molecular mechanisms and signaling pathways remain unclear. While overexpression reduces both insulin-stimulated MAP kinase and Akt activation, its absence does not affect insulin signaling or GLUT4 trafficking. Confers resistance to dietary obesity. May act by regulating AKT2, but not AKT1, phosphorylation at the plasma membrane. Part of a signaling pathway that regulates actin cytoskeleton remodeling. Required for the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation. Participates in regulation of cortical and submembraneous actin by hydrolyzing PtdIns(3,4,5)P3 thereby regulating membrane ruffling. Regulates cell adhesion and cell spreading. Required for HGF-mediated lamellipodium formation, cell scattering and spreading. Acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation. Acts as a regulator of neuritogenesis by regulating PtdIns(3,4,5)P3 level and is required to form an initial protrusive pattern, and later, maintain proper neurite outgrowth. Acts as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A). Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Involved in EGF signaling pathway. Upon stimulation by EGF, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3. Plays a negative role in regulating the PI3K-PKB pathway, possibly by inhibiting PKB activity. Down-regulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1. In macrophages, down-regulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor (M-CSF)-induced signaling. Plays a role in the localization of AURKA and NEDD9/HEF1 to the basolateral membrane at interphase in polarized cysts, thereby mediates cell cycle homeostasis, cell polarization and cilia assembly. Additionally promotion of cilia growth is also facilitated by hydrolysis of (PtdIns(3,4,5)P3) to PtdIns(3,4)P2. Promotes formation of apical membrane-initiation sites during the initial stages of lumen formation via Rho family-induced actin filament organization and CTNNB1 localization to cell-cell contacts. May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6. Involved in endochondral ossification.
• Tissue Specificity: Widely expressed, most prominently in skeletal muscle, heart and brain. Present in platelets. Expressed in transformed myeloid cells and in primary macrophages, but not in peripheral blood monocytes.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
  B cell receptor sig.ling pathway (hsa04662)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Insulin sig.ling pathway (hsa04910)
• Reactome Pathway:
  Synthesis of IP3 and IP4 in the cytosol (R-HSA-1855204)
  Interleukin receptor SHC signaling (R-HSA-912526)
  Signaling by CSF1 (M-CSF) in myeloid cells (R-HSA-9680350)
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
• BioCyc Pathway: MetaCyc:HS09233-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric neoplasm	DISOKN4Y	Definitive	Altered Expression	[1]
Hepatitis B virus infection	DISLQ2XY	Definitive	Altered Expression	[2]
Opsismodysplasia	DIS26539	Definitive	Autosomal recessive	[3]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Biomarker	[4]
Acute erythroid leukemia	DISZFC1O	Strong	Altered Expression	[5]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[6]
Alzheimer disease	DISF8S70	Strong	Biomarker	[7]
Atrial fibrillation	DIS15W6U	Strong	Altered Expression	[8]
Bone disease	DISE1F82	Strong	Biomarker	[9]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[10]
Colon cancer	DISVC52G	Strong	Biomarker	[11]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[11]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[13]
Depression	DIS3XJ69	Strong	Altered Expression	[14]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[15]
Essential hypertension	DIS7WI98	Strong	Genetic Variation	[16]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[17]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[6]
Gonorrhea	DISQ5AO6	Strong	Altered Expression	[18]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[19]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Insulinoma	DISIU1JS	Strong	Biomarker	[20]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[15]
Neoplasm	DISZKGEW	Strong	Biomarker	[21]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[22]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[15]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[23]
Obesity	DIS47Y1K	Strong	Biomarker	[24]
Osteoporosis-pseudoglioma syndrome	DISIXWT1	Strong	Genetic Variation	[25]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[26]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[17]
Turner syndrome	DIS2035C	Strong	Biomarker	[27]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[28]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[21]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[21]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Biomarker	[29]
Stroke	DISX6UHX	moderate	Genetic Variation	[30]
Schneckenbecken dysplasia	DIS2NNB4	Supportive	Autosomal recessive	[31]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[29]
High blood pressure	DISY2OHH	Limited	Altered Expression	[15]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[32]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[33]

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 Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[34]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[41]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[44]

10 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 Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[35]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[37]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[38]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[39]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[40]
AMG 176	DM0Q7NO	Phase 1	AMG 176 decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[42]
AZD5991	DM7QGHO	Phase 1	AZD5991 decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[42]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[45]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (INPPL1).	[46]

References

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• [23] PLEK2 mediates metastasis and vascular invasion via the ubiquitin-dependent degradation of SHIP2 in non-small cell lung cancer.Int J Cancer. 2020 May 1;146(9):2563-2575. doi: 10.1002/ijc.32675. Epub 2019 Nov 6.
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