Modulating the activity of the Src Homology 2 (SH2) — containing Inositol 5′-Phosphatase (SHIP) enzyme family with small molecule inhibitors provides a useful and unconventional method of influencing cell signaling in the PI3K pathway. The development of small molecules that selectively target one of the SHIP paralogs (SHIP1 or SHIP2) as well as inhibitors that simultaneously target both enzymes have provided promising data linking the phosphatase activity of the SHIP enzymes to disorders and disease states that are in dire need of new therapeutic targets. These include cancer, immunotherapy, diabetes, obesity, and Alzheimer's disease. In this mini-review, we will provide a brief overview of research in these areas that support targeting SHIP1, SHIP2 or both enzymes for therapeutic purposes.
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Cover Image
Cover Image
The cover image depicts a combination of a 3D reconstruction of ER-TGN contact sites by focus ion beam-scanning electron microscopy (FIB-SEM) and five images showing the visualization of the contacts by FRET/FLIM. The 3D reconstruction of the Golgi stack was generated from FIB-SEM tomography of a HepG2 cell using IMOD software. The ER cisterna is shown in red (with ribosomes as white circles), while the trans-most cisterna of the Golgi stack is shown in green (with emerging clathrin-coated buds decorated by pink dots). The five FLIM images are from HeLa cells expressing a TGN reporter (TGN46-GFP) and an ER reporter (mCherry-Cb5). The pseudocolour scale represents donor (i.e. GFP) lifetime (τ) values ranging from 1.8 (blue) to 2.7 ns (red) under conditions that destabilize (left) or stabilize ER-TGN contact sites. For further information, see the review by Venditti and colleagues (pp. 187–197). Image courtesy of Maria Antonietta De Matteis.
Small molecule targeting of SHIP1 and SHIP2
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