Tensin-4-Dependent MET Stabilization Is Essential for Survival and Proliferation in Carcinoma Cells

Ghaffar Muharram, Pranshu Sahgal, Taina Korpela, Nicola de Franceschi, Riina Kaukonen, Katherine Clark, David Tulasne, Olli Carpén, Johanna Ivaska (Corresponding Author)

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Abstract

Inappropriate MET tyrosine kinase receptor signaling is detected in almost all types of human cancer and contributes to malignant growth and MET dependency via proliferative and antiapoptotic activities. Independently, Tensin-4 (TNS4) is emerging as a putative oncogene in many cancer types, but the mechanisms of TNS4 oncogenic activity are not well established. Here, we demonstrate that TNS4 directly interacts with phosphorylated MET via the TNS4 SH2-domain to positively regulate cell survival, proliferation, and migration, through increased MET protein stability. In addition, TNS4 interaction with ß1-integrin cytoplasmic tail positively regulates ß1-integrin stability. Loss of TNS4 or disruption of MET-TNS4 interaction triggers MET trafficking toward the lysosomal compartment that is associated with excessive degradation of MET and triggers MET-addicted carcinoma cell death in vitro and in vivo. Significant correlation between MET and TNS4 expression in human colon carcinoma and ovarian carcinoma suggests TNS4 plays a critical role in MET stability in cancer.
Original languageEnglish
Pages (from-to)421-436
JournalDevelopmental Cell
Volume29
Issue number4
DOIs
Publication statusPublished - 2014
MoE publication typeA1 Journal article-refereed

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Stabilization
Cells
Carcinoma
Integrins
Survival
Proto-Oncogene Proteins c-met
Cell proliferation
Cell death
Degradation
Tensins
Neoplasms
Proteins
src Homology Domains
Protein Stability
Oncogenes
Cell Movement
Tail
Cell Survival
Colon
Cell Death

Cite this

Muharram, G., Sahgal, P., Korpela, T., de Franceschi, N., Kaukonen, R., Clark, K., ... Ivaska, J. (2014). Tensin-4-Dependent MET Stabilization Is Essential for Survival and Proliferation in Carcinoma Cells. Developmental Cell, 29(4), 421-436. https://doi.org/10.1016/j.devcel.2014.03.024
Muharram, Ghaffar ; Sahgal, Pranshu ; Korpela, Taina ; de Franceschi, Nicola ; Kaukonen, Riina ; Clark, Katherine ; Tulasne, David ; Carpén, Olli ; Ivaska, Johanna. / Tensin-4-Dependent MET Stabilization Is Essential for Survival and Proliferation in Carcinoma Cells. In: Developmental Cell. 2014 ; Vol. 29, No. 4. pp. 421-436.
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abstract = "Inappropriate MET tyrosine kinase receptor signaling is detected in almost all types of human cancer and contributes to malignant growth and MET dependency via proliferative and antiapoptotic activities. Independently, Tensin-4 (TNS4) is emerging as a putative oncogene in many cancer types, but the mechanisms of TNS4 oncogenic activity are not well established. Here, we demonstrate that TNS4 directly interacts with phosphorylated MET via the TNS4 SH2-domain to positively regulate cell survival, proliferation, and migration, through increased MET protein stability. In addition, TNS4 interaction with {\ss}1-integrin cytoplasmic tail positively regulates {\ss}1-integrin stability. Loss of TNS4 or disruption of MET-TNS4 interaction triggers MET trafficking toward the lysosomal compartment that is associated with excessive degradation of MET and triggers MET-addicted carcinoma cell death in vitro and in vivo. Significant correlation between MET and TNS4 expression in human colon carcinoma and ovarian carcinoma suggests TNS4 plays a critical role in MET stability in cancer.",
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Muharram, G, Sahgal, P, Korpela, T, de Franceschi, N, Kaukonen, R, Clark, K, Tulasne, D, Carpén, O & Ivaska, J 2014, 'Tensin-4-Dependent MET Stabilization Is Essential for Survival and Proliferation in Carcinoma Cells', Developmental Cell, vol. 29, no. 4, pp. 421-436. https://doi.org/10.1016/j.devcel.2014.03.024

Tensin-4-Dependent MET Stabilization Is Essential for Survival and Proliferation in Carcinoma Cells. / Muharram, Ghaffar; Sahgal, Pranshu; Korpela, Taina; de Franceschi, Nicola; Kaukonen, Riina; Clark, Katherine; Tulasne, David; Carpén, Olli; Ivaska, Johanna (Corresponding Author).

In: Developmental Cell, Vol. 29, No. 4, 2014, p. 421-436.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Muharram, Ghaffar

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AU - Korpela, Taina

AU - de Franceschi, Nicola

AU - Kaukonen, Riina

AU - Clark, Katherine

AU - Tulasne, David

AU - Carpén, Olli

AU - Ivaska, Johanna

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AB - Inappropriate MET tyrosine kinase receptor signaling is detected in almost all types of human cancer and contributes to malignant growth and MET dependency via proliferative and antiapoptotic activities. Independently, Tensin-4 (TNS4) is emerging as a putative oncogene in many cancer types, but the mechanisms of TNS4 oncogenic activity are not well established. Here, we demonstrate that TNS4 directly interacts with phosphorylated MET via the TNS4 SH2-domain to positively regulate cell survival, proliferation, and migration, through increased MET protein stability. In addition, TNS4 interaction with ß1-integrin cytoplasmic tail positively regulates ß1-integrin stability. Loss of TNS4 or disruption of MET-TNS4 interaction triggers MET trafficking toward the lysosomal compartment that is associated with excessive degradation of MET and triggers MET-addicted carcinoma cell death in vitro and in vivo. Significant correlation between MET and TNS4 expression in human colon carcinoma and ovarian carcinoma suggests TNS4 plays a critical role in MET stability in cancer.

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