INPP4B: the New Kid on the PI3K Block

Irina U Agoulnik,Myles C Hodgson,Michael M Ittmann,Wayne A Bowden

doi:10.18632/oncotarget.260

Irina U Agoulnik, Myles C Hodgson + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.260

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Abstract

Dysregulation of phosphatidyl inositol signaling occurs in many cancers and other disorders. The lipid and protein phosphatase, PTEN (Phosphatase and Tensin homology protein on chromosome 10), is a known tumor suppressor whose function is frequently lost in various malignancies due to mutations in the coding region or genomic deletions. Recently, another lipid phosphatase, Inositol Polyphosphate 4-phosphatase type II (INPP4B), has emerged as a potential tumor suppressor in prostate, breast, and ovarian cancers and possibly in leukemia. We will review its structure and function, crosstalk with androgen receptor signaling, and regulation of INPP4B expression, as well as existing data about its role in cancer.

Highlights

INPP4B is one of many enzymes maintaining tight homeostasis of phosphoinositides in the cell
Phosphorylation of Akt at T308 is associated with corecruitment of Akt and PDK1 to PI(3,4,5)P3 at the plasma membrane and S473 phosphorylation has been attributed to the activity of mTORC2 [8]
In human mammary epithelial cells (HMEC) and breast cancer cell lines INPP4B was able to suppress both basal [17] and IGF induced Akt phosphorylation [5], anchorage independent growth, invasion, and motility. Depletion of both INPP4B and PTEN in HMECs resulted in cellular senescence, which could be alleviated by knockdown of p53 [5]

Summary

B CKSAKDRT

The recruitment of effector proteins to specific cellular membranes. A Golgi specific isoform of INPP4B has been identified [1], but it remains to be determined what specific functions this isoform performs within the cell. Constitutive activation of another member of the forkhead box family, FOXO3a, can enhance AR transactivation and increase endogenous AR protein levels in LNCaP cells [36] This complexity of AR regulation by Akt downstream targets may contribute to the differences observed in different cellular contexts. Another study found that PTEN-mediated suppression of AR function in PC-3 cells was dependent on protein expression of the Akt target FOXO1a [39] These observations suggest that PTEN may regulate AR through both modulating Akt activity and direct interaction. In HMECs and breast cancer cell lines INPP4B was able to suppress both basal [17] and IGF induced Akt phosphorylation [5], anchorage independent growth, invasion, and motility Depletion of both INPP4B and PTEN in HMECs resulted in cellular senescence, which could be alleviated by knockdown of p53 [5]. Based on both clinical and biological evidence INPP4B appears to be a tumor suppressor gene in prostate cancer and is inactivated at rates similar to the classic tumor suppressor gene PTEN

Concluding remarks

Findings

Methods