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

Nir Ben-Chetrit; David Chetrit; Roslin Russell; Cindy Körner; 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; Ferna Milanezi; Marc Symons; Rotem Ben-Hamo; Sol Efroni; Ferno 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

Nir Ben-Chetrit, David Chetrit, Roslin Russell, Cindy Körner, 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, Ferna Milanezi, Marc Symons, Rotem Ben-Hamo, Sol Efroni, Ferno Schmitt, Stefan Wiemann, Carlos Caldas, Marcelo Ehrlich, Yosef Yarden

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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
State	Published - 20 Jan 2015

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© 2015, American Association for the Advancement of Science. All rights reserved.

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Ben-Chetrit, N., Chetrit, D., Russell, R., Körner, 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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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, N, Chetrit, D, Russell, R, Körner, 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, R, 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, Nir

AU - Chetrit, David

AU - Russell, Roslin

AU - Körner, 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, Ferna

AU - Symons, Marc

AU - Ben-Hamo, Rotem

AU - Efroni, Sol

AU - Schmitt, Ferno

AU - Wiemann, Stefan

AU - Caldas, Carlos

AU - Ehrlich, Marcelo

AU - Yarden, Yosef

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

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