Drosophila PRL-1 Is a Growth Inhibitor That Counteracts the Function of the Src Oncogene

Krystle T Pagarigan,Leslie J Saucedo,Travis K Rahe,Bryce W Bunn,Julie F Weis,Jake Goodchild,Madhuri Kango-Singh

doi:10.1371/journal.pone.0061084

Krystle T Pagarigan, Leslie J Saucedo + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0061084

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Journal: PloS one	Publication Date: Apr 8, 2013
Citations: 17	License type: CC BY 4.0

Affiliation: University of Puget Sound, Fred Hutch Cancer Center

Abstract

Phosphatase of Regenerating Liver (PRL) family members have emerged as molecular markers that significantly correlate to the ability of many cancers to metastasize. However, contradictory cellular responses to PRL expression have been reported, including the inhibition of cell cycle progression. An obvious culprit for the discrepancy is the use of dozens of different cell lines, including many isolated from tumors or cultured cells selected for immortalization which may have missing or mutated modulators of PRL function. We created transgenic Drosophila to study the effects of PRL overexpression in a genetically controlled, organismal model. Our data support the paradigm that the normal cellular response to high levels of PRL is growth suppression and furthermore, that PRL can counter oncogenic activity of Src. The ability of PRL to inhibit growth under normal conditions is dependent on a CAAX motif that is required to localize PRL to the apical edge of the lateral membrane. However, PRL lacking the CAAX motif can still associate indiscriminately with the plasma membrane and retains its ability to inhibit Src function. We propose that PRL binds to other membrane-localized proteins that are effectors of Src or to Src itself. This first examination of PRL in a model organism demonstrates that PRL performs as a tumor suppressor and underscores the necessity of identifying the conditions that enable it to transform into an oncogene in cancer.

Highlights

In the past decade, Phosphatase of Regenerating Liver (PRL) family members have been touted as molecular markers that significantly correlate to the ability of cancers to metastasize [1],[2],[3]
Drosophila PRL-1 inhibits growth The Drosophila genome encodes a single PRL protein, which is highly similar (74–76%) to all three human PRLs and contains the three domains shown to be required for PRL function in mammals: a Dual Specific Phosphatase (DSP) active site (HCxxGxxR) [9],[12],[13],[15],[48], an aspartate (Asp77) that has been demonstrated to facilitate phosphate transfer [58], and a Cterminal, membrane-targeting CAAX motif adjacent to a polybasic region [48,49,50,51]
Overexpression of dPRL-1 broadly resulted in inhibition of growth that in some instances resulted in lethality

Summary

Introduction

Phosphatase of Regenerating Liver (PRL) family members have been touted as molecular markers that significantly correlate to the ability of cancers to metastasize [1],[2],[3]. Studies in cell culture indicate that exogenous expression of PRLs can induce cell proliferation [7],[9],[10],[11], migration [12],[13],[14], and invasiveness [12],[11],[14]. Constitutive expression of PRL1 and -3 enable cultured cells to form tumors when injected into mice [12],[15],[13]. PRL-3 first gained notoriety as a marker for metastasis when the Vogelstein lab found PRL-3 levels highly elevated in 100% of colon cancer metastases as compared to nonmetastatic tumors and normal colon epithelial [16].

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