Inhibition of PRL-2·CNNM3 Protein Complex Formation Decreases Breast Cancer Proliferation and Tumor Growth

Kostantin, Elie; Hardy, Serge; Valinsky, William C.; Kompatscher, Andreas; Baaij, Jeroen H. F. de; Zolotarov, Yevgen; Landry, Melissa; Uetani, Noriko; Martínez-Cruz, Luis Alfonso; Hoenderop, Joost G. J.; Shrier, Alvin; Tremblay, Michel L.

doi:10.1074/jbc.m115.705863

Cited by 40 publications

(61 citation statements)

References 50 publications

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“…3) that is transmitted to the preceding region of the polypeptide chain. These data enhance the key role played by L553-559 and are in agreement with our recent observations demonstrating that substitution of Asp-426 in CNNM3 (homolog of Asp-558 in CNNM2) results in losing the ability of this protein to interact with PRL-2 (41). Interestingly, the overexpression of the CNNM3 D426A mutant in cancer cells is known to decrease their ability to proliferate under magnesium-deprived situation, demonstrating a …”

Section: Cnnm2supporting

confidence: 80%

“…In support of this, we found that the single substitution of the conserved aspartate residue located at the tip of the extended loop in at least two members of the CNNM family (Asp-558-CNNM2; Asp-426-CNNM3) has similar consequences and completely abolishes the CNNM/PRL interaction ( Fig. 3) (41).…”

Section: Discussionsupporting

confidence: 59%

“…PRL-2⅐CNNM3 complex-dependent oncogenic advantage in a more stringent environment (41). However, the main changes occurring in PRL-1 are in loops configuring the walls of the catalytic cavity as follows: the P-loop (residues 103-110), the WPD-loop (residues 68 -77), the TI-loop (residues 137-143), and the ␤3␣2-loop (residues 48 -55) (Fig.…”

Section: Cnnm2mentioning

confidence: 99%

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Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2

Giménez-Mascarell

Oyenarte

Hardy

et al. 2017

Journal of Biological Chemistry

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Edited by Roger J. ColbranPhosphatases of regenerating liver (PRLs), the most oncogenic of all protein-tyrosine phosphatases (PTPs), play a critical role in metastatic progression of cancers. Recent findings established a new paradigm by uncovering that their association with magnesium transporters of the cyclin M (CNNM) family causes a rise in intracellular magnesium levels that promote oncogenic transformation. Recently, however, essential roles for regulation of the circadian rhythm and reproduction of the CNNM family have been highlighted. Here, we describe the crystal structure of PRL-1 in complex with the Bateman module of CNNM2 (CNNM2 BAT ), which consists of two cystathionine ␤-synthase (CBS) domains (IPR000664) and represents an intracellular regulatory module of the transporter. The structure reveals a heterotetrameric association, consisting of a disclike homodimer of CNNM2 BAT bound to two independent PRL-1 molecules, each one located at opposite tips of the disc. The structure highlights the key role played by Asp-558 at the extended loop of the CBS2 motif of CNNM2 in maintaining the association between the two proteins and proves that the interaction between CNNM2 and PRL-1 occurs via the catalytic domain of the phosphatase. Our data shed new light on the structural basis underlying the interaction between PRL phosphatases and CNNM transporters and provides a hypothesis about the molecular mechanism by which PRL-1, upon binding to CNNM2, might increase the intracellular concentration of Mg 2؉ thereby contributing to tumor progression and metastasis. The availability of this structure sets the basis for the rational design of compounds modulating PRL-1 and CNNM2 activities.

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Section: Cnnm2supporting

confidence: 80%

Section: Discussionsupporting

confidence: 59%

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Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2

Giménez-Mascarell

Oyenarte

Hardy

et al. 2017

Journal of Biological Chemistry

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“…Although oncogenic properties of the PRLs leave no doubt, neither biological substrates nor physiological functions have been clearly demonstrated until recently. Notably, previous studies revealed that PRL1, -2, and -3 control intracellular Mg 2+ levels by interacting with the Mg 2+ transporter of the cyclin M (CNNM) family (8,9), and the interaction between PRL2 and CNNM3 is required to promote breast tumor growth through a Mg 2+ -dependent mechanism (10). These findings paved the way to the understanding of PRL functions in a normal physiological context, especially in Mg 2+ -dependent cellular processes.…”

Section: Introductionmentioning

confidence: 93%

PRL2 links magnesium flux and sex-dependent circadian metabolic rhythms

et al. 2017

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“…Thienopyridone can induce cancer cell anoikis, which is a type of programmed cell death initiated by p130 Cas cleavage. Thienopyridone also prevents the association of PRLs with CNNMs (39). Most recently, a more potent derivative of thienopyridone, Analog 13, has been developed, which showed IC50 values of 50, 52 and 18 nmol/L against PRL1, PRL2, and PRL3 respectively (40).…”

Section: Proof Of Concept For Targeting the Prl Phosphatasesmentioning

confidence: 99%

Therapeutic Targeting of Oncogenic Tyrosine Phosphatases

et al. 2017

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Protein tyrosine phosphatases (PTP) are exciting and novel targets for cancer drug discovery that work in concert with protein tyrosine kinases (PTK) in controlling cellular homeostasis. Given the activating role that some PTKs play in initiating growth factor-mediated cellular processes, PTPs are usually perceived as the negative regulators of these events and therefore tumor suppressive in nature. However, mounting evidence indicate that PTPs do not always antagonize the activity of PTKs in regulating tyrosine phosphorylation, but can also play dominant roles in the initiation and progression of signaling cascades that regulate cell functions. It follows, therefore, that PTP malfunction can actively contribute to a host of human disorders, in particular, cancer, metabolic syndromes, and autoimmune diseases. The Src homology domain containing phosphatase 2 (SHP2) and the three-membered family of phosphatases of regenerating liver (PRL) are infamously oncogenic members of the PTP superfamily. Both are established regulators of major cancer pathways such as Ras/ ERK1/2, Src, JAK/STAT, JNK, NF-κB, and PTEN/PI3K/AKT. Furthermore, upregulation, mutation, or other dysregulation of these PTPs has been positively correlated with cancer initiation and progression. This review will provide topical coverage of target validation and drug discovery efforts made in targeting these oncogenic PTPs as compelling candidates for cancer therapy.

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Inhibition of PRL-2·CNNM3 Protein Complex Formation Decreases Breast Cancer Proliferation and Tumor Growth

Cited by 40 publications

References 50 publications

Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2

Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2

PRL2 links magnesium flux and sex-dependent circadian metabolic rhythms

Therapeutic Targeting of Oncogenic Tyrosine Phosphatases

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