Synaptojanin 2 is a druggable mediator of metastasis and the gene is overexpressed and amplified in breast cancer

Chetrit, Nir Ben Chetrit; David Chetrit; Roslin Russell; Cindy Koerner; Maicol Mancini; Ali Abdul-Hai; Tomer Itkin; Silvia Carvalho; Hadas Cohen-Dvashi; Wolfgang J. Koestler; Kirti Shukla; Moshit Lindzen; Merav Kedmi; Mattia Lauriola; Ziv Shulman; Haim Barr; Dalia Seger; Daniela A. Ferraro; Fresia Pareja; Hava Gil-Henn; Tsvee Lapidot; Ronen Alon; Fernanda Milanezi; Marc Symons; Hamo, Rotem Ben Hamo; Sol Efroni; Fernando Schmitt; Stefan Wiemann; Carlos Caldas; Marcelo Ehrlich; Yosef Yarden

doi:10.1126/scisignal.2005537

Synaptojanin 2 is a druggable mediator of metastasis and the gene is overexpressed and amplified in breast cancer

Chetrit, Nir Ben Chetrit, David Chetrit, Roslin Russell, Cindy Koerner, Maicol Mancini, Ali Abdul-Hai, Tomer Itkin, Silvia Carvalho, Hadas Cohen-Dvashi, Wolfgang J. Koestler, Kirti Shukla, Moshit Lindzen, Merav Kedmi, Mattia Lauriola, Ziv Shulman, Haim Barr, Dalia Seger, Daniela A. Ferraro, Fresia Pareja, Hava Gil-HennTsvee Lapidot, Ronen Alon, Fernanda Milanezi, Marc Symons, Hamo, Rotem Ben Hamo, Sol Efroni, Fernando Schmitt, Stefan Wiemann, Carlos Caldas, Marcelo Ehrlich, Yosef Yarden

Research output: Contribution to journal › Article › peer-review

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Abstract

Amplified HER2, which encodes a member of the epidermal growth factor receptor (EGFR) family, is a target of effective therapies against breast cancer. In search for similarly targetable genomic aberrations, we identified copy number gains in SYNJ2, which encodes the 5′-inositol lipid phosphatase synaptojanin 2, as well as overexpression in a small fraction of human breast tumors. Copy gain and overexpression correlated with shorter patient survival and a low abundance of the tumor suppressor microRNA miR-31. SYNJ2 promoted cell migration and invasion in culture and lung metastasis of breast tumor xenografts in mice. Knocking down SYNJ2 impaired the endocytic recycling of EGFR and the formation of cellular lamellipodia and invadopodia. Screening compound libraries identified SYNJ2-specific inhibitors that prevented cell migration but did not affect the related neural protein SYNJ1, suggesting that SYNJ2 is a potentially druggable target to block cancer cell migration.

Original language	English
Article number	ra7
Journal	Science Signaling
Volume	8
Issue number	360
DOIs	https://doi.org/10.1126/scisignal.2005537
Publication status	Published - 20 Jan 2015

Funding

This work was performed at the Marvin Tanner Laboratory for Cancer Research. We thank L. Rameh, T. Takenawa, S. Lavi, M. Katz, I. Amit, A. Citri, Y. Peleg, S. Albeck, Y. Jacobovitch, A. Plotnikov, C. Wirth, and E. Muenstermann for their kind help. Funding: Our research is supported by the National Cancer Institute, the European Research Council, the Seventh Framework Program of the European Commission, the German-Israeli Project Cooperation (DIP), the Israel Cancer Research Fund, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair. Author contributions: N.B.-C., D.C., M.E., and Y.Y. conceived the study. N.B.-C., D.C., C.K., M.M., A.A.-H., T.I., S.C., H.C.-D., W.J.K., K.S., M. Lauriola, M.K., M. Lindzen, Z.S., H.B., D.S., D.A.F., F.P., and F.M. performed experiments. R.R., R.B.-H., S.E., F.S., and C.C. analyzed patient data. H.G.-H., T.L., R.A., S.W., M.E., and Y.Y. supervised experiments. M.S. provided reagents. N.B.-C., M.E., and Y.Y. wrote the manuscript.

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Biology
Cell Biology

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Ben Chetrit, C. N., Chetrit, D., Russell, R., Koerner, C., Mancini, M., Abdul-Hai, A., Itkin, T., Carvalho, S., Cohen-Dvashi, H., Koestler, W. J., Shukla, K., Lindzen, M., Kedmi, M., Lauriola, M., Shulman, Z., Barr, H., Seger, D., Ferraro, D. A., Pareja, F., ... Yarden, Y. (2015). Synaptojanin 2 is a druggable mediator of metastasis and the gene is overexpressed and amplified in breast cancer. Science Signaling, 8(360), Article ra7. https://doi.org/10.1126/scisignal.2005537

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title = "Synaptojanin 2 is a druggable mediator of metastasis and the gene is overexpressed and amplified in breast cancer",

abstract = "Amplified HER2, which encodes a member of the epidermal growth factor receptor (EGFR) family, is a target of effective therapies against breast cancer. In search for similarly targetable genomic aberrations, we identified copy number gains in SYNJ2, which encodes the 5′-inositol lipid phosphatase synaptojanin 2, as well as overexpression in a small fraction of human breast tumors. Copy gain and overexpression correlated with shorter patient survival and a low abundance of the tumor suppressor microRNA miR-31. SYNJ2 promoted cell migration and invasion in culture and lung metastasis of breast tumor xenografts in mice. Knocking down SYNJ2 impaired the endocytic recycling of EGFR and the formation of cellular lamellipodia and invadopodia. Screening compound libraries identified SYNJ2-specific inhibitors that prevented cell migration but did not affect the related neural protein SYNJ1, suggesting that SYNJ2 is a potentially druggable target to block cancer cell migration.",

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Ben Chetrit, CN, Chetrit, D, Russell, R, Koerner, C, Mancini, M, Abdul-Hai, A, Itkin, T, Carvalho, S , Cohen-Dvashi, H, Koestler, WJ, Shukla, K, Lindzen, M, Kedmi, M, Lauriola, M, Shulman, Z , Barr, H, Seger, D, Ferraro, DA, Pareja, F, Gil-Henn, H, Lapidot, T , Alon, R, Milanezi, F, Symons, M, Ben Hamo, HR, Efroni, S, Schmitt, F, Wiemann, S, Caldas, C, Ehrlich, M & Yarden, Y 2015, 'Synaptojanin 2 is a druggable mediator of metastasis and the gene is overexpressed and amplified in breast cancer', Science Signaling, vol. 8, no. 360, ra7. https://doi.org/10.1126/scisignal.2005537

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AU - Ben Chetrit, Chetrit, Nir

AU - Chetrit, David

AU - Russell, Roslin

AU - Koerner, Cindy

AU - Mancini, Maicol

AU - Abdul-Hai, Ali

AU - Itkin, Tomer

AU - Carvalho, Silvia

AU - Cohen-Dvashi, Hadas

AU - Koestler, Wolfgang J.

AU - Shukla, Kirti

AU - Lindzen, Moshit

AU - Kedmi, Merav

AU - Lauriola, Mattia

AU - Shulman, Ziv

AU - Barr, Haim

AU - Seger, Dalia

AU - Ferraro, Daniela A.

AU - Pareja, Fresia

AU - Gil-Henn, Hava

AU - Lapidot, Tsvee

AU - Alon, Ronen

AU - Milanezi, Fernanda

AU - Symons, Marc

AU - Ben Hamo, Hamo, Rotem

AU - Efroni, Sol

AU - Schmitt, Fernando

AU - Wiemann, Stefan

AU - Caldas, Carlos

AU - Ehrlich, Marcelo

AU - Yarden, Yosef

PY - 2015/1/20

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N2 - Amplified HER2, which encodes a member of the epidermal growth factor receptor (EGFR) family, is a target of effective therapies against breast cancer. In search for similarly targetable genomic aberrations, we identified copy number gains in SYNJ2, which encodes the 5′-inositol lipid phosphatase synaptojanin 2, as well as overexpression in a small fraction of human breast tumors. Copy gain and overexpression correlated with shorter patient survival and a low abundance of the tumor suppressor microRNA miR-31. SYNJ2 promoted cell migration and invasion in culture and lung metastasis of breast tumor xenografts in mice. Knocking down SYNJ2 impaired the endocytic recycling of EGFR and the formation of cellular lamellipodia and invadopodia. Screening compound libraries identified SYNJ2-specific inhibitors that prevented cell migration but did not affect the related neural protein SYNJ1, suggesting that SYNJ2 is a potentially druggable target to block cancer cell migration.

AB - Amplified HER2, which encodes a member of the epidermal growth factor receptor (EGFR) family, is a target of effective therapies against breast cancer. In search for similarly targetable genomic aberrations, we identified copy number gains in SYNJ2, which encodes the 5′-inositol lipid phosphatase synaptojanin 2, as well as overexpression in a small fraction of human breast tumors. Copy gain and overexpression correlated with shorter patient survival and a low abundance of the tumor suppressor microRNA miR-31. SYNJ2 promoted cell migration and invasion in culture and lung metastasis of breast tumor xenografts in mice. Knocking down SYNJ2 impaired the endocytic recycling of EGFR and the formation of cellular lamellipodia and invadopodia. Screening compound libraries identified SYNJ2-specific inhibitors that prevented cell migration but did not affect the related neural protein SYNJ1, suggesting that SYNJ2 is a potentially druggable target to block cancer cell migration.

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DO - 10.1126/scisignal.2005537

M3 - Article

SN - 1945-0877

VL - 8

JO - Science Signaling

JF - Science Signaling

IS - 360

M1 - ra7

ER -

Synaptojanin 2 is a druggable mediator of metastasis and the gene is overexpressed and amplified in breast cancer

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