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Spotlight

Phosphoinositide signaling in cancer: INPP4B Akt(s) out John F. Woolley1,2*, Irakli Dzneladze2,3*, and Leonardo Salmena1,2 1

Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada Princess Margaret Cancer Centre, University Health Network, Toronto, Canada 3 Department of Medical Biophysics, University of Toronto, Toronto, Canada 2

INPP4B acts as a tumor suppressor in various epithelial cancers by inhibiting PI3K/Akt signaling. Unexpectedly, tumor-promoting features of INPP4B in leukemia and breast cancer have been recently uncovered. In this spotlight, we discuss the seemingly paradoxical nature of INPP4B-mediated signaling in cancer.

INPP4B: The orthodox A phosphoinositide (PI) is membrane-bound inositol-lipid that acts as docking sites for signaling proteins involved in regulating numerous cellular processes including proliferation, survival, and apoptosis. The reversible phosphorylation status at the 30 -, 40 - and 50 - positions of the PI inositol rings dictates what downstream signaling molecules are recruited. INPP4B plays an important role in this dynamic equilibrium by dephosphorylating the 40 -position of PI(3,4)P2 to generate PI(3)P (reviewed in [1]). PI(3,4)P2, like PI(3,4,5)P3, is necessary for the activation of Akt, a potent driver of tumorigenic cell growth, therefore INPP4B was hypothesized to be a tumor suppressor protein akin to PTEN, which dephosphorylates PI(3,4,5)P3. The first experimental evidence demonstrating this was from a high throughput RNA interference-based screen which identified INPP4B as a suppressor of mammary epithelial cell transformation [2]. A suppressive role for INPP4B in cancer was later confirmed in two separate studies demonstrating that INPP4B knockdown in breast cancer cells results in enhanced Akt activation, cell proliferation, anchorage independent growth and enhanced motility [3,4]. Overexpression of INPP4B in mammary cells reduced tumor growth in mouse xenografts [3,4]. Clinically these studies demonstrated that loss of INPP4B expression in both breast and ovarian cancer was associated with decreased patient survival [3,4]. Similar to breast cancer, the observed loss of INPP4B expression in some prostate cancer patients was associated with a decreased time to relapse, while in vitro INPP4B depletion produced increased proliferation and Akt activation [5]. Among several other tissues, INPP4B has been recently been demonstrated to act as a bona fide tumor suppressor gene in human and mouse thyroid tissue [6,7]. Although Corresponding author: Salmena, L. ([email protected]). Keywords: INPP4B; phosphoinositide; PI3K; Akt; oncogene; tumor suppressor. * These authors contributed equally to this work. 1471-4914/ ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2015.06.006

several mechanisms by which INPP4B functions in the cell have been described, the predominant mechanism remains its ability to decrease cellular levels of PI(3,4)P2, and thereby inhibit Akt activation. INPP4B: The paradox To date, there is abundant evidence supporting the hypothesis that INPP4B plays a tumor suppressor role akin to PTEN in cancer. However, unexpected findings from recent reports indicate that INPP4B function may be more complicated: one study of more than 24 cancer types revealed that SGK3 amplification is associated with INPP4B overexpression in some breast cancers [8]. SGK3 is known to be essential for breast cancer cell growth and survival in PI3KCA-mutant cells that have reduced Akt-dependent signaling capacity. Interestingly, the product of INPP4B phosphatase activity, PI(3)P, binds the PX domain of SGK3, localizing it to endosomal membranes. While exploring a mechanism of SGK3 signaling downstream of PI3K in breast cancer, Gasser et al. discovered that INPP4B was a critical mediator of this pathway. Indeed RNAi knockdown of INPP4B prevented IGF-1 dependent phosphorylation of SGK-3, which is essential for SGK-3 catalytic activity [8]. SGK3, in cooperation with GSK3b phosphorylates the tumor-suppressor NDRG1 resulting in its ubiquitination and proteasomal degradation. This PI3K/INPP4B/SGK3/NDRG1 axis reportedly drives migration, anchorage-independent growth and 3D-colony formation in vitro as well as xenograft tumor development [8]. This role for INPP4B in promoting an oncogenic signaling pathway is in direct contrast with previous understanding of INPP4B as a tumor suppressor in breast cancer [3,4]. The authors here focus on an interesting effector protein in NDRG1, but given that SGK3 and Akt kinases share several substrates, there are likely to be other possible targets of this pathway. More recently, two independent studies have linked INPP4B with poor outcomes in acute myeloid leukemia (AML) [9,10]. In both studies INPP4B was overexpressed in a subset of AML patients with lower complete response rates to chemotherapy, shorter leukemia-free survival, and inferior overall survival. In multivariate analyses, INPP4B emerged as an independent prognostic marker for survival in AML, with hazard ratios potentially worse than those observed in patients with FLT3-ITD mutations [9]. Further investigation, in vivo and in vitro, showed that INPP4B overexpression drives colony formation, proliferation and drug-resistance [9,10]. However, these two studies provide Trends in Molecular Medicine xx (2015) 1–3

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AKT

Breast cancer [2,3,4]

AKT Thyroid Cancer [6,7] Knockout of INPP4B can promote follicular-like thyroid cancer progression and metastasis in the context of PTEN haploinsufficiency

INPP4B-loss phenotype consistent with tumor suppressor funcon; expression restricted to ER-posive mammary epithelial cells; loss of INPP4B protein is a marker of aggressive basal-like breast carcinomas

AKT Breast cancer [8] Evidence for tumor promong role of INPP4B in context of elevated SGK3 acvaon; INPP4B regulates oncogenic SGK3 signaling

Ovarian cancer [3] Copy number losses observed at INPP4B locus; low INPP4B protein levels associated with lymph node metastasis and decreased paent survival

Prostate cancer [5]

AKT Leukemia [9,10] INPP4B is a new prognosc marker in acute myeloid leukemia (AML); elevated expression associates with a tumor promong role in AML cells and chemotherapy resistance phenotypes

AKT

INPP4B is an androgen responsive gene; depleon of INPP4B reduced me to relapse

Key:

AKT Clinical survival

Colony formaon/3D growth

Mouse model

Migraon/ Metastasis

Proliferaon

AKT acvaon

Drug-/ radiaonresistance

Anchorageindependent growth

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Figure 1. Dual role of INPP4B in human cancer. INPP4B was initially shown to act as a tumor suppressor in ovarian, prostate, laryngeal, and some breast cancer. However, recent evidence has emerged suggesting a very different role in leukemia and some breast cancers. In these studies INPP4B appears to enhance cancer traits such as proliferation, metastasis and drug resistance. This undoubtedly confounds INPP4B’s identity as a de facto tumor suppressor akin to PTEN.

a contrasting explanation of the mechanism underlying this apparent oncogenic capacity of INPP4B. Rijal et al. show that overexpression of a catalytically-inactive form of INPP4B induces a chemoresistant phenotype, suggesting a phosphatase-independent function of INPP4B in AML [10]. However, Dzneladze et al. show that INPP4B-mediated proliferation, colony formation and chemoresistance rely on a catalytically active protein [9]. The findings by Rijal et al. [10] suggest that INPP4B may be acting as an adaptor protein; it has previously been suggested that INPP5B/SHIP-1 activity and PTEN nuclear function may be mediated by non-catalytic adapter functions. A similar effect could also be relevant for INPP4B biology. Notably, a common feature of the three above studies is an apparent dispensability of Akt function in mediating INPP4B associated oncogenic phenotypes [8–10]. This points to a novel route for INPP4B to elicit its function, independent of its canonical role in blocking PI3K pathway signaling. Gasser et al. provide one potential mechanism for this is via SGK3. This study provides critical insight into the need for the enzymatic function of INPP4B whereby its product, PI(3)P, localizes the effector kinase SGK3 into the vicinity of the substrate [8]. Thus INPP4B does not merely regulate Akt homeostasis through inactivation of its substrate PI(3,4)P2, but it also has a positive effect on 2

signaling via its catalytic product PI(3)P. The complex nature of survival signaling in cancer cells should make such findings less surprising, and opposing roles for proteins is not unheard of, thus these data highlight the need for a better understanding of the underlying biochemistry of INPP4B in order to fully appreciate its function (Figure 1). Overall, INPP4B, like its famous cousin PTEN, is emerging as an important and more dynamic player in the cancer world. Currently there are several mechanisms that have been reported to explain INPP4B function as tumor suppressor. In this spotlight we muddy the waters further by describing a recently identified oncogenic function, and possibly a mechanism to explain this new phenotype. References 1 Bunney, T.D. and Katan, M. (2010) Phosphoinositide signalling in cancer: beyond PI3K and PTEN. Nat. Rev. Cancer 10, 342–352 2 Westbrook, T.F. et al. (2005) A genetic screen for candidate tumor suppressors identifies REST. Cell 121, 837–848 3 Gewinner, C. et al. (2009) Evidence that inositol polyphosphate 4phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 16, 115–125 4 Fedele, C.G. et al. (2010) Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc. Natl. Acad. Sci. U.S.A. 107, 22231–22236

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Spotlight 5 Hodgson, M.C. et al. (2011) Decreased expression and androgen regulation of the tumor suppressor gene INPP4B in prostate cancer. Cancer Res. 71, 572–582 6 Kofuji, S. et al. (2015) INPP4B is a PtdIns(3,4,5)P3 phosphatase that can act as a tumor suppressor. Cancer Discov. Published online April 16, 2015. http://dx.doi.org/10.1158/2159-8290.CD-14-1329 7 Chew, C.L. et al. (2015) In vivo role of INPP4B in tumor and metastasis suppression through regulation of PI3K/AKT signaling at endosomes. Cancer Discov. Published online April 16, 2015. http://dx.doi.org/ 10.1158/2159-8290.CD-14-1347

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8 Gasser, J.a. et al. (2014) SGK3 Mediates INPP4B-Dependent PI3K Signaling in Breast Cancer. Mol. Cell 56, 595–607 9 Dzneladze, I. et al. (2015) INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia. Leukemia Published online March 4, 2015. http://dx.doi.org/10.1038/ leu.2015.51 10 Rijal, S. et al. (2015) Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML. Blood 125, 2815–2824

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Phosphoinositide signaling in cancer: INPP4B Akt(s) out.

INPP4B acts as a tumor suppressor in various epithelial cancers by inhibiting PI3K/Akt signaling. Unexpectedly, tumor-promoting features of INPP4B in ...
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