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. Author manuscript; available in PMC: 2019 Mar 18.
Published in final edited form as: Oncogene. 2018 Sep 18;38(7):1121–1135. doi: 10.1038/s41388-018-0498-3

Figure 7. INPP4B loss activates Akt and PKC signaling and leads to resistance of castration therapies.

Figure 7.

Loss of INPP4B activity in primary prostate cancer (3) leads to accumulation of its substrates PI(3,4)P2 and PI(4,5)P2 which activate Akt and PKC respectively. Activation of Akt and PKC kinases increase phosphorylation of both full length AR and AR splice variants stimulating their nuclear translocation, transcriptional activation and reprogramming, and ligand-independent transcriptional activity. Castration elevates levels of AR splice variants (73) and decreases androgen-dependent INPP4B expression (74), further activating Akt and PKC signaling pathways and leading to resistance to castration therapies. Unlike full length AR, AR-V7 is unable to induce INPP4B expression and may interfere with androgen dependent induction of INPP4B expression