Am J Cancer Res 2013;3(3):290-301
Original Article
Identification of two regions in the p140Cap adaptor protein that re-tain the
ability to suppress tumor cell properties
Nanaocha Sharma, Daniele Repetto, Simona Aramu, Silvia Grasso, Isabella Russo, Arianna Fiorentino, Maurizia Mello-Grand,
Sara Cabodi, Vijay Singh, Giovanna Chiorino, Emilia Turco, Paola Di Stefano, Paola Defilippi
Department of Molecular Biotechnology and Health Sciences, Università degli Studi di Torino, Via Nizza 52, Torino Italy;
Fondazione Edo ed Elvo Tempia, Cancer Genomics Lab, Biella, Italy. Emilia Turco, Paola Di Stefano and Paola Defilippi are
co-last authors.
Received April 24, 2013; Accepted May 30, 2013; Epub June 20, 2013; Published June 30, 2013
Abstract: p140Cap is an adaptor protein that negatively controls tumor cell properties, by inhibiting in vivo tumor growth and
metastasis formation. Our previous data demonstrated that p140Cap interferes with tumor growth and impairs invasive
properties of cancer cells inactivating signaling pathways, such as the tyrosine kinase Src or E-cadherin/EGFR cross-talk. In
breast cancer p140Cap expression inversely correlates with tumor malignancy. p140Cap is composed of several conserved
domains that mediate association with specific partners. Here we focus our attention on two domains of p140Cap, the TER
(Tyrosine Enriched Region) which includes several tyrosine residues, and the CT (Carboxy Terminal) which contains a proline
rich sequence, involved in binding to SH2 and SH3 domains, respectively. By generating stable cell lines expressing these two
proteins, we demonstrate that both TER and CT domains maintain the ability to associate the C-terminal Src kinase (Csk) and
Src, to inhibit Src activation and Focal adhesion kinase (Fak) phosphorylation, and to impair in vitro and in vivo tumor cell
features. In particular expression of TER and CT proteins in cancer cells inhibits in vitro and in vivo growth and directional
migration at a similar extent of the full length p140Cap protein. Moreover, by selective point mutations and deletion we show that
the ability of the modules to act as negative regulators of cell migration and proliferation mainly resides on the two tyrosines (Y)
inserted in the EPLYA and EGLYA sequences in the TER module and in the second proline-rich stretch contained in the CT
protein. Gene signature of cells expressing p140Cap, TER or CT lead to the identification of a common pattern of 105
down-regulated and 128 up-regulated genes, suggesting that the three proteins can act through shared pathways. Overall, this
work highlights that the TER and CT regions of p140Cap can efficiently suppress tumor cell properties, opening the perspective
that short, defined p140Cap regions can have therapeutic effects. (ajcr0000199).
Keywords: p140Cap, breast cancer, lung cancer, colon cancer, cell signaling, Csk, Src
Address correspondence to: Dr. Paola Defilippi, Molecular Biotechnology Center, University of Torino, Via Nizza 52 - 10126
Torino, Italy. Phone: +39-0116706434; Fax: +39-0116706432; E-mail: paola.defilippi@unito.it
Original Article
Identification of two regions in the p140Cap adaptor protein that re-tain the
ability to suppress tumor cell properties
Nanaocha Sharma, Daniele Repetto, Simona Aramu, Silvia Grasso, Isabella Russo, Arianna Fiorentino, Maurizia Mello-Grand,
Sara Cabodi, Vijay Singh, Giovanna Chiorino, Emilia Turco, Paola Di Stefano, Paola Defilippi
Department of Molecular Biotechnology and Health Sciences, Università degli Studi di Torino, Via Nizza 52, Torino Italy;
Fondazione Edo ed Elvo Tempia, Cancer Genomics Lab, Biella, Italy. Emilia Turco, Paola Di Stefano and Paola Defilippi are
co-last authors.
Received April 24, 2013; Accepted May 30, 2013; Epub June 20, 2013; Published June 30, 2013
Abstract: p140Cap is an adaptor protein that negatively controls tumor cell properties, by inhibiting in vivo tumor growth and
metastasis formation. Our previous data demonstrated that p140Cap interferes with tumor growth and impairs invasive
properties of cancer cells inactivating signaling pathways, such as the tyrosine kinase Src or E-cadherin/EGFR cross-talk. In
breast cancer p140Cap expression inversely correlates with tumor malignancy. p140Cap is composed of several conserved
domains that mediate association with specific partners. Here we focus our attention on two domains of p140Cap, the TER
(Tyrosine Enriched Region) which includes several tyrosine residues, and the CT (Carboxy Terminal) which contains a proline
rich sequence, involved in binding to SH2 and SH3 domains, respectively. By generating stable cell lines expressing these two
proteins, we demonstrate that both TER and CT domains maintain the ability to associate the C-terminal Src kinase (Csk) and
Src, to inhibit Src activation and Focal adhesion kinase (Fak) phosphorylation, and to impair in vitro and in vivo tumor cell
features. In particular expression of TER and CT proteins in cancer cells inhibits in vitro and in vivo growth and directional
migration at a similar extent of the full length p140Cap protein. Moreover, by selective point mutations and deletion we show that
the ability of the modules to act as negative regulators of cell migration and proliferation mainly resides on the two tyrosines (Y)
inserted in the EPLYA and EGLYA sequences in the TER module and in the second proline-rich stretch contained in the CT
protein. Gene signature of cells expressing p140Cap, TER or CT lead to the identification of a common pattern of 105
down-regulated and 128 up-regulated genes, suggesting that the three proteins can act through shared pathways. Overall, this
work highlights that the TER and CT regions of p140Cap can efficiently suppress tumor cell properties, opening the perspective
that short, defined p140Cap regions can have therapeutic effects. (ajcr0000199).
Keywords: p140Cap, breast cancer, lung cancer, colon cancer, cell signaling, Csk, Src
Address correspondence to: Dr. Paola Defilippi, Molecular Biotechnology Center, University of Torino, Via Nizza 52 - 10126
Torino, Italy. Phone: +39-0116706434; Fax: +39-0116706432; E-mail: paola.defilippi@unito.it
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American Journal of Cancer Research
| ISSN: 2156-6976 |