SHIP2 and its involvement in various diseases.
BACKGROUND
Inositol polyphosphate 5-phosphatase (SHIP2) is an important negative regulator of intracellular phosphatidylinositol phosphate, a key second messenger of various intracellular signaling pathways. The functional upregulation of SHIP2 results in signaling blockade, leading to related disorders.


METHODS
We first summarize the role of SHIP2 in the regulation of insulin signaling and type 2 diabetes, including remarkable advances in pharmacological approaches. In addition, this review highlights new findings regarding the involvement of SHIP2 in a number of diseases, including cancer, neurodegenerative diseases, and atherosclerosis.


RESULTS
Recently identified small-molecule inhibitors of SHIP2 phosphatase activity emphasize the potential therapeutic value of SHIP2. In addition, currently available evidence demonstrates the importance of the scaffolding-type protein function of SHIP2. Understanding this interesting function will help clarify the complicated involvement of SHIP2 in various disorders.


CONCLUSIONS
Recent studies have demonstrated that SHIP2 is a promising therapeutic target for not only type 2 diabetes, but also cancer, neurodegenerative diseases, and atherosclerosis. Targeting SHIP2 through specific small-molecule inhibitors will have beneficial effects on these diseases.
Astellas Pharma, Inc., Pharmacology Research Labs, Drug Discovery Research, 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. akira.suwa@jp.astellas.com
Akira
A
Suwa
Takeshi
T
Kurama
Teruhiko
T
Shimokawa
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000503:physiopathology; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007328:Insulin / Q000819:agonists / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000503:physiopathology; D018129:Phosphatidylinositol Phosphates / Q000819:agonists / Q000502:physiology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary; D015290:Second Messenger Systems / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D007328:Insulin; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases