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Ribosomal protein S6 kinase (RSK)-2 as a central effector molecule in RON receptor tyrosine kinase mediated epithelial to mesenchymal transition induced by macrophage-stimulating protein.
Mol Cancer 2011; 10:66MC

Abstract

BACKGROUND

Epithelial to mesenchymal transition (EMT) occurs during cancer cell invasion and malignant metastasis. Features of EMT include spindle-like cell morphology, loss of epithelial cellular markers and gain of mesenchymal phenotype. Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein (MSP) has been implicated in cellular EMT program; however, the major signaling determinant(s) responsible for MSP-induced EMT is unknown.

RESULTS

The study presented here demonstrates that RSK2, a downstream signaling protein of the Ras-Erk1/2 pathway, is the principal molecule that links MSP-activated RON signaling to complete EMT. Using MDCK cells expressing RON as a model, a spindle-shape based screen was conducted, which identifies RSK2 among various intracellular proteins as a potential signaling molecule responsible for MSP-induced EMT. MSP stimulation dissociated RSK2 with Erk1/2 and promoted RSK2 nuclear translocation. MSP strongly induced RSK2 phosphorylation in a dose-dependent manner. These effects relied on RON and Erk1/2 phosphorylation, which is significantly potentiated by transforming growth factor (TGF)-β1, an EMT-inducing cytokine. Specific RSK inhibitor SL0101 completely prevented MSP-induced RSK phosphorylation, which results in inhibition of MSP-induced spindle-like morphology and suppression of cell migration associated with EMT. In HT-29 cancer cells that barely express RSK2, forced RSK2 expression results in EMT-like phenotype upon MSP stimulation. Moreover, specific siRNA-mediated silencing of RSK2 but not RSK1 in L3.6pl pancreatic cancer cells significantly inhibited MSP-induced EMT-like phenotype and cell migration.

CONCLUSIONS

MSP-induced RSK2 activation is a critical determinant linking RON signaling to cellular EMT program. Inhibition of RSK2 activity may provide a therapeutic opportunity for blocking RON-mediated cancer cell migration and subsequent invasion.

Authors+Show Affiliations

Division of Cancer Biology at State Key Laboratory for Diagnosis & Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou 310003, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21619683

Citation

Ma, Qi, et al. "Ribosomal Protein S6 Kinase (RSK)-2 as a Central Effector Molecule in RON Receptor Tyrosine Kinase Mediated Epithelial to Mesenchymal Transition Induced By Macrophage-stimulating Protein." Molecular Cancer, vol. 10, 2011, p. 66.
Ma Q, Guin S, Padhye SS, et al. Ribosomal protein S6 kinase (RSK)-2 as a central effector molecule in RON receptor tyrosine kinase mediated epithelial to mesenchymal transition induced by macrophage-stimulating protein. Mol Cancer. 2011;10:66.
Ma, Q., Guin, S., Padhye, S. S., Zhou, Y. Q., Zhang, R. W., & Wang, M. H. (2011). Ribosomal protein S6 kinase (RSK)-2 as a central effector molecule in RON receptor tyrosine kinase mediated epithelial to mesenchymal transition induced by macrophage-stimulating protein. Molecular Cancer, 10, p. 66. doi:10.1186/1476-4598-10-66.
Ma Q, et al. Ribosomal Protein S6 Kinase (RSK)-2 as a Central Effector Molecule in RON Receptor Tyrosine Kinase Mediated Epithelial to Mesenchymal Transition Induced By Macrophage-stimulating Protein. Mol Cancer. 2011 May 28;10:66. PubMed PMID: 21619683.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ribosomal protein S6 kinase (RSK)-2 as a central effector molecule in RON receptor tyrosine kinase mediated epithelial to mesenchymal transition induced by macrophage-stimulating protein. AU - Ma,Qi, AU - Guin,Sunny, AU - Padhye,Snehal S, AU - Zhou,Yong-Qing, AU - Zhang,Rui-Wen, AU - Wang,Ming-Hai, Y1 - 2011/05/28/ PY - 2011/02/01/received PY - 2011/05/28/accepted PY - 2011/5/31/entrez PY - 2011/5/31/pubmed PY - 2011/9/21/medline SP - 66 EP - 66 JF - Molecular cancer JO - Mol. Cancer VL - 10 N2 - BACKGROUND: Epithelial to mesenchymal transition (EMT) occurs during cancer cell invasion and malignant metastasis. Features of EMT include spindle-like cell morphology, loss of epithelial cellular markers and gain of mesenchymal phenotype. Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein (MSP) has been implicated in cellular EMT program; however, the major signaling determinant(s) responsible for MSP-induced EMT is unknown. RESULTS: The study presented here demonstrates that RSK2, a downstream signaling protein of the Ras-Erk1/2 pathway, is the principal molecule that links MSP-activated RON signaling to complete EMT. Using MDCK cells expressing RON as a model, a spindle-shape based screen was conducted, which identifies RSK2 among various intracellular proteins as a potential signaling molecule responsible for MSP-induced EMT. MSP stimulation dissociated RSK2 with Erk1/2 and promoted RSK2 nuclear translocation. MSP strongly induced RSK2 phosphorylation in a dose-dependent manner. These effects relied on RON and Erk1/2 phosphorylation, which is significantly potentiated by transforming growth factor (TGF)-β1, an EMT-inducing cytokine. Specific RSK inhibitor SL0101 completely prevented MSP-induced RSK phosphorylation, which results in inhibition of MSP-induced spindle-like morphology and suppression of cell migration associated with EMT. In HT-29 cancer cells that barely express RSK2, forced RSK2 expression results in EMT-like phenotype upon MSP stimulation. Moreover, specific siRNA-mediated silencing of RSK2 but not RSK1 in L3.6pl pancreatic cancer cells significantly inhibited MSP-induced EMT-like phenotype and cell migration. CONCLUSIONS: MSP-induced RSK2 activation is a critical determinant linking RON signaling to cellular EMT program. Inhibition of RSK2 activity may provide a therapeutic opportunity for blocking RON-mediated cancer cell migration and subsequent invasion. SN - 1476-4598 UR - https://www.unboundmedicine.com/medline/citation/21619683/Ribosomal_protein_S6_kinase__RSK__2_as_a_central_effector_molecule_in_RON_receptor_tyrosine_kinase_mediated_epithelial_to_mesenchymal_transition_induced_by_macrophage_stimulating_protein_ L2 - https://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-10-66 DB - PRIME DP - Unbound Medicine ER -