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Phosphorylation of KIBRA by the extracellular signal-regulated kinase (ERK)-ribosomal S6 kinase (RSK) cascade modulates cell proliferation and migration.
Cell Signal. 2014 Feb; 26(2):343-51.CS

Abstract

In mammals, KIBRA is defined as a memory performance-associated protein. The physiological function and regulation of KIBRA in non-neuronal cells are much less understood. Recent studies have identified KIBRA as a novel regulator of the Hippo signaling pathway, which plays a critical role in tumorigenesis by inhibiting cell proliferation and promoting apoptosis. We recently reported that KIBRA is phosphorylated by the mitotic kinases Aurora and cyclin-dependent kinase 1 during mitosis. In this current study, we show that KIBRA is also phosphorylated by the ERK (extracellular signal-regulated kinases)-RSK (p90 ribosomal S6 kinases) cascade. We demonstrated that ERK1/2 phosphorylate KIBRA at Ser(548) in cells as well as in vitro. Moreover, we found that RSK1/2 specifically phosphorylates KIBRA at two highly conserved sites (Thr(929) and Ser(947)) in vitro and in cells. RSK-mediated phosphorylation is required for KIBRA binding to RSK1, but not RSK2. Surprisingly, KIBRA knockdown impaired cell migration and proliferation in breast cancer cells. By using inducible-expression cell lines, we further show that phospho-regulation of KIBRA by ERK1/2 and RSK1/2 is required for proper cell proliferation and RSK-mediated phosphorylation also modulates KIBRA's migratory activity in MDA-MB-231 breast cancer cells. Our findings uncover unexpected results and a new mechanism through which KIBRA regulates cell migration and proliferation.

Authors+Show Affiliations

The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.Department of Molecular Nephrology, University Hospital Münster, Germany.Department of Molecular Nephrology, University Hospital Münster, Germany.The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: dongj@unmc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

24269383

Citation

Yang, Shuping, et al. "Phosphorylation of KIBRA By the Extracellular Signal-regulated Kinase (ERK)-ribosomal S6 Kinase (RSK) Cascade Modulates Cell Proliferation and Migration." Cellular Signalling, vol. 26, no. 2, 2014, pp. 343-51.
Yang S, Ji M, Zhang L, et al. Phosphorylation of KIBRA by the extracellular signal-regulated kinase (ERK)-ribosomal S6 kinase (RSK) cascade modulates cell proliferation and migration. Cell Signal. 2014;26(2):343-51.
Yang, S., Ji, M., Zhang, L., Chen, Y., Wennmann, D. O., Kremerskothen, J., & Dong, J. (2014). Phosphorylation of KIBRA by the extracellular signal-regulated kinase (ERK)-ribosomal S6 kinase (RSK) cascade modulates cell proliferation and migration. Cellular Signalling, 26(2), 343-51. https://doi.org/10.1016/j.cellsig.2013.11.012
Yang S, et al. Phosphorylation of KIBRA By the Extracellular Signal-regulated Kinase (ERK)-ribosomal S6 Kinase (RSK) Cascade Modulates Cell Proliferation and Migration. Cell Signal. 2014;26(2):343-51. PubMed PMID: 24269383.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phosphorylation of KIBRA by the extracellular signal-regulated kinase (ERK)-ribosomal S6 kinase (RSK) cascade modulates cell proliferation and migration. AU - Yang,Shuping, AU - Ji,Ming, AU - Zhang,Lin, AU - Chen,Yuanhong, AU - Wennmann,Dirk Oliver, AU - Kremerskothen,Joachim, AU - Dong,Jixin, Y1 - 2013/11/19/ PY - 2013/09/29/received PY - 2013/11/06/revised PY - 2013/11/14/accepted PY - 2013/11/26/entrez PY - 2013/11/26/pubmed PY - 2014/8/19/medline KW - CDK1 KW - ERK1/2 KW - KIBRA KW - MAPK KW - Migration KW - Phosphorylation KW - Proliferation KW - RSK1/2 KW - WW and C2 domain containing proteins KW - WWC KW - cyclin-dependent kinase 1 KW - extracellular signal-regulated kinases 1/2 KW - mitogen-activated protein kinases KW - p90 ribosomal S6 kinases 1/2 SP - 343 EP - 51 JF - Cellular signalling JO - Cell. Signal. VL - 26 IS - 2 N2 - In mammals, KIBRA is defined as a memory performance-associated protein. The physiological function and regulation of KIBRA in non-neuronal cells are much less understood. Recent studies have identified KIBRA as a novel regulator of the Hippo signaling pathway, which plays a critical role in tumorigenesis by inhibiting cell proliferation and promoting apoptosis. We recently reported that KIBRA is phosphorylated by the mitotic kinases Aurora and cyclin-dependent kinase 1 during mitosis. In this current study, we show that KIBRA is also phosphorylated by the ERK (extracellular signal-regulated kinases)-RSK (p90 ribosomal S6 kinases) cascade. We demonstrated that ERK1/2 phosphorylate KIBRA at Ser(548) in cells as well as in vitro. Moreover, we found that RSK1/2 specifically phosphorylates KIBRA at two highly conserved sites (Thr(929) and Ser(947)) in vitro and in cells. RSK-mediated phosphorylation is required for KIBRA binding to RSK1, but not RSK2. Surprisingly, KIBRA knockdown impaired cell migration and proliferation in breast cancer cells. By using inducible-expression cell lines, we further show that phospho-regulation of KIBRA by ERK1/2 and RSK1/2 is required for proper cell proliferation and RSK-mediated phosphorylation also modulates KIBRA's migratory activity in MDA-MB-231 breast cancer cells. Our findings uncover unexpected results and a new mechanism through which KIBRA regulates cell migration and proliferation. SN - 1873-3913 UR - https://www.unboundmedicine.com/medline/citation/24269383/Phosphorylation_of_KIBRA_by_the_extracellular_signal_regulated_kinase__ERK__ribosomal_S6_kinase__RSK__cascade_modulates_cell_proliferation_and_migration_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0898-6568(13)00343-4 DB - PRIME DP - Unbound Medicine ER -