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Epidermal growth factor stimulates RSK2 activation through activation of the MEK/ERK pathway and src-dependent tyrosine phosphorylation of RSK2 at Tyr-529.
J Biol Chem. 2008 Feb 22; 283(8):4652-7.JB

Abstract

The Ser/Thr kinase ribosomal S6 kinase 2 (RSK2) has been demonstrated to phosphorylate transcription factor CREB (cyclic AMP-responsive-binding protein) and histone H3 in response to mitogenic stimulation by epidermal growth factor (EGF). EGF activates the MEK/ERK pathway to activate RSK2. We recently reported that receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) directly tyrosine phosphorylates RSK2 at Tyr-529, which consequently regulates RSK2 activation by facilitating inactive ERK binding to RSK2 that is required for ERK-dependent phosphorylation and activation of RSK2 (Kang, S., Dong, S., Gu, T. L., Guo, A., Cohen, M. S., Lonial, S., Khoury, H. J., Fabbro, D., Gilliland, D. G., Bergsagel, P. L., Taunton, J., Polakiewicz, R. D., and Chen, J. (2007) Cancer Cell 12, 201-214). Here we report that upon treatment of EGF, RSK2 was tyrosine-phosphorylated at Tyr-529 and activated in 293T and COS7 cells that do not express FGFR3. In contrast to FGFR3, the receptor tyrosine kinase EGF receptor did not directly phosphorylate RSK2 at Tyr-529 in an in vitro kinase assay using recombinant RSK2 and active EGF receptor or FGFR3. By mass spectroscopy-based studies, we identified Src tyrosine kinase family members Src and Fyn as upstream kinases of RSK2 Tyr-529. Treatment of Src inhibitor PP2 effectively attenuated EGF-dependent activation and Tyr-529 phosphorylation of RSK2, suggesting that Src family members are the kinases that phosphorylate RSK2 at Tyr-529 in response to EGF. Src and Fyn were able to directly phosphorylate RSK2 at Tyr-529 in the in vitro kinase assay. In vitro reconstitution of Tyr-529 phosphorylation by Src in glutathione S-transferase-tagged RSK2 enhanced inactive ERK binding to RSK2 wild type, but not the Y529F mutant. Together, our findings suggest that Src-dependent phosphorylation at Tyr-529 facilitates inactive ERK binding to RSK2, which might be a general requirement for RSK2 activation by EGF through the MEK/ERK pathway.

Authors+Show Affiliations

Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.No affiliation info availableNo affiliation info availableNo 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

Language

eng

PubMed ID

18156174

Citation

Kang, Sumin, et al. "Epidermal Growth Factor Stimulates RSK2 Activation Through Activation of the MEK/ERK Pathway and Src-dependent Tyrosine Phosphorylation of RSK2 at Tyr-529." The Journal of Biological Chemistry, vol. 283, no. 8, 2008, pp. 4652-7.
Kang S, Dong S, Guo A, et al. Epidermal growth factor stimulates RSK2 activation through activation of the MEK/ERK pathway and src-dependent tyrosine phosphorylation of RSK2 at Tyr-529. J Biol Chem. 2008;283(8):4652-7.
Kang, S., Dong, S., Guo, A., Ruan, H., Lonial, S., Khoury, H. J., Gu, T. L., & Chen, J. (2008). Epidermal growth factor stimulates RSK2 activation through activation of the MEK/ERK pathway and src-dependent tyrosine phosphorylation of RSK2 at Tyr-529. The Journal of Biological Chemistry, 283(8), 4652-7.
Kang S, et al. Epidermal Growth Factor Stimulates RSK2 Activation Through Activation of the MEK/ERK Pathway and Src-dependent Tyrosine Phosphorylation of RSK2 at Tyr-529. J Biol Chem. 2008 Feb 22;283(8):4652-7. PubMed PMID: 18156174.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Epidermal growth factor stimulates RSK2 activation through activation of the MEK/ERK pathway and src-dependent tyrosine phosphorylation of RSK2 at Tyr-529. AU - Kang,Sumin, AU - Dong,Shaozhong, AU - Guo,Ailan, AU - Ruan,Hong, AU - Lonial,Sagar, AU - Khoury,Hanna Jean, AU - Gu,Ting-Lei, AU - Chen,Jing, Y1 - 2007/12/21/ PY - 2007/12/25/pubmed PY - 2008/4/11/medline PY - 2007/12/25/entrez SP - 4652 EP - 7 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 283 IS - 8 N2 - The Ser/Thr kinase ribosomal S6 kinase 2 (RSK2) has been demonstrated to phosphorylate transcription factor CREB (cyclic AMP-responsive-binding protein) and histone H3 in response to mitogenic stimulation by epidermal growth factor (EGF). EGF activates the MEK/ERK pathway to activate RSK2. We recently reported that receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) directly tyrosine phosphorylates RSK2 at Tyr-529, which consequently regulates RSK2 activation by facilitating inactive ERK binding to RSK2 that is required for ERK-dependent phosphorylation and activation of RSK2 (Kang, S., Dong, S., Gu, T. L., Guo, A., Cohen, M. S., Lonial, S., Khoury, H. J., Fabbro, D., Gilliland, D. G., Bergsagel, P. L., Taunton, J., Polakiewicz, R. D., and Chen, J. (2007) Cancer Cell 12, 201-214). Here we report that upon treatment of EGF, RSK2 was tyrosine-phosphorylated at Tyr-529 and activated in 293T and COS7 cells that do not express FGFR3. In contrast to FGFR3, the receptor tyrosine kinase EGF receptor did not directly phosphorylate RSK2 at Tyr-529 in an in vitro kinase assay using recombinant RSK2 and active EGF receptor or FGFR3. By mass spectroscopy-based studies, we identified Src tyrosine kinase family members Src and Fyn as upstream kinases of RSK2 Tyr-529. Treatment of Src inhibitor PP2 effectively attenuated EGF-dependent activation and Tyr-529 phosphorylation of RSK2, suggesting that Src family members are the kinases that phosphorylate RSK2 at Tyr-529 in response to EGF. Src and Fyn were able to directly phosphorylate RSK2 at Tyr-529 in the in vitro kinase assay. In vitro reconstitution of Tyr-529 phosphorylation by Src in glutathione S-transferase-tagged RSK2 enhanced inactive ERK binding to RSK2 wild type, but not the Y529F mutant. Together, our findings suggest that Src-dependent phosphorylation at Tyr-529 facilitates inactive ERK binding to RSK2, which might be a general requirement for RSK2 activation by EGF through the MEK/ERK pathway. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/18156174/Epidermal_growth_factor_stimulates_RSK2_activation_through_activation_of_the_MEK/ERK_pathway_and_src_dependent_tyrosine_phosphorylation_of_RSK2_at_Tyr_529_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=18156174 DB - PRIME DP - Unbound Medicine ER -