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Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression.
J Clin Invest. 2013 Mar; 123(3):1157-75.JCI

Abstract

Concurrent activation of RAS/ERK and PI3K/AKT pathways is implicated in prostate cancer progression. The negative regulators of these pathways, including sprouty2 (SPRY2), protein phosphatase 2A (PP2A), and phosphatase and tensin homolog (PTEN), are commonly inactivated in prostate cancer. The molecular basis of cooperation between these genetic alterations is unknown. Here, we show that SPRY2 deficiency alone triggers activation of AKT and ERK, but this is insufficient to drive tumorigenesis. In addition to AKT and ERK activation, SPRY2 loss also activates a PP2A-dependent tumor suppressor checkpoint. Mechanistically, the PP2A-mediated growth arrest depends on GSK3β and is ultimately mediated by nuclear PTEN. In murine prostate cancer models, Pten haploinsufficiency synergized with Spry2 deficiency to drive tumorigenesis, including metastasis. Together, these results show that loss of Pten cooperates with Spry2 deficiency by bypassing a novel tumor suppressor checkpoint. Furthermore, loss of SPRY2 expression correlates strongly with loss of PTEN and/or PP2A subunits in human prostate cancer. This underlines the cooperation between SPRY2 deficiency and PTEN or PP2A inactivation in promoting tumorigenesis. Overall, we propose SPRY2, PTEN, and PP2A status as an important determinant of prostate cancer progression. Characterization of this trio may facilitate patient stratification for targeted therapies and chemopreventive interventions.

Authors+Show Affiliations

The Beatson Institute for Cancer Research, Glasgow, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23434594

Citation

Patel, Rachana, et al. "Sprouty2, PTEN, and PP2A Interact to Regulate Prostate Cancer Progression." The Journal of Clinical Investigation, vol. 123, no. 3, 2013, pp. 1157-75.
Patel R, Gao M, Ahmad I, et al. Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression. J Clin Invest. 2013;123(3):1157-75.
Patel, R., Gao, M., Ahmad, I., Fleming, J., Singh, L. B., Rai, T. S., McKie, A. B., Seywright, M., Barnetson, R. J., Edwards, J., Sansom, O. J., & Leung, H. Y. (2013). Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression. The Journal of Clinical Investigation, 123(3), 1157-75. https://doi.org/10.1172/JCI63672
Patel R, et al. Sprouty2, PTEN, and PP2A Interact to Regulate Prostate Cancer Progression. J Clin Invest. 2013;123(3):1157-75. PubMed PMID: 23434594.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression. AU - Patel,Rachana, AU - Gao,Meiling, AU - Ahmad,Imran, AU - Fleming,Janis, AU - Singh,Lukram B, AU - Rai,Taranjit Singh, AU - McKie,Arthur B, AU - Seywright,Morag, AU - Barnetson,Robert J, AU - Edwards,Joanne, AU - Sansom,Owen J, AU - Leung,Hing Y, Y1 - 2013/02/22/ PY - 2012/03/12/received PY - 2013/01/03/accepted PY - 2013/2/26/entrez PY - 2013/2/26/pubmed PY - 2013/5/15/medline SP - 1157 EP - 75 JF - The Journal of clinical investigation JO - J. Clin. Invest. VL - 123 IS - 3 N2 - Concurrent activation of RAS/ERK and PI3K/AKT pathways is implicated in prostate cancer progression. The negative regulators of these pathways, including sprouty2 (SPRY2), protein phosphatase 2A (PP2A), and phosphatase and tensin homolog (PTEN), are commonly inactivated in prostate cancer. The molecular basis of cooperation between these genetic alterations is unknown. Here, we show that SPRY2 deficiency alone triggers activation of AKT and ERK, but this is insufficient to drive tumorigenesis. In addition to AKT and ERK activation, SPRY2 loss also activates a PP2A-dependent tumor suppressor checkpoint. Mechanistically, the PP2A-mediated growth arrest depends on GSK3β and is ultimately mediated by nuclear PTEN. In murine prostate cancer models, Pten haploinsufficiency synergized with Spry2 deficiency to drive tumorigenesis, including metastasis. Together, these results show that loss of Pten cooperates with Spry2 deficiency by bypassing a novel tumor suppressor checkpoint. Furthermore, loss of SPRY2 expression correlates strongly with loss of PTEN and/or PP2A subunits in human prostate cancer. This underlines the cooperation between SPRY2 deficiency and PTEN or PP2A inactivation in promoting tumorigenesis. Overall, we propose SPRY2, PTEN, and PP2A status as an important determinant of prostate cancer progression. Characterization of this trio may facilitate patient stratification for targeted therapies and chemopreventive interventions. SN - 1558-8238 UR - https://www.unboundmedicine.com/medline/citation/23434594/Sprouty2_PTEN_and_PP2A_interact_to_regulate_prostate_cancer_progression_ L2 - https://doi.org/10.1172/JCI63672 DB - PRIME DP - Unbound Medicine ER -