Tags

Type your tag names separated by a space and hit enter

p90 RSK2 mediates antianoikis signals by both transcription-dependent and -independent mechanisms.
Mol Cell Biol. 2013 Jul; 33(13):2574-85.MC

Abstract

How invasive and metastatic tumor cells evade anoikis induction remains unclear. We found that knockdown of RSK2 sensitizes diverse cancer cells to anoikis induction, which is mediated through phosphorylation targets including apoptosis signal-regulating kinase 1 (ASK1) and cyclic AMP (cAMP) response element-binding protein (CREB). We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. Moreover, the RSK2→CREB signaling pathway provides antianoikis protection by regulating gene expression of protein effectors that are involved in cell death regulation, including the antiapoptotic factor protein tyrosine kinase 6 (PTK6) and the proapoptotic factor inhibitor-of-growth protein 3 (ING3). PTK6 overexpression or ING3 knockdown in addition to ASK1 knockdown further rescued the increased sensitivity to anoikis induction in RSK2 knockdown cells. These data together suggest that RSK2 functions as a signal integrator to provide antianoikis protection to cancer cells in both transcription-independent and -dependent manners, in part by signaling through ASK1 and CREB, and contributes to cancer cell invasion and tumor metastasis.

Authors+Show Affiliations

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo 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
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23608533

Citation

Jin, Lingtao, et al. "P90 RSK2 Mediates Antianoikis Signals By Both Transcription-dependent and -independent Mechanisms." Molecular and Cellular Biology, vol. 33, no. 13, 2013, pp. 2574-85.
Jin L, Li D, Lee JS, et al. P90 RSK2 mediates antianoikis signals by both transcription-dependent and -independent mechanisms. Mol Cell Biol. 2013;33(13):2574-85.
Jin, L., Li, D., Lee, J. S., Elf, S., Alesi, G. N., Fan, J., Kang, H. B., Wang, D., Fu, H., Taunton, J., Boggon, T. J., Tucker, M., Gu, T. L., Chen, Z. G., Shin, D. M., Khuri, F. R., & Kang, S. (2013). P90 RSK2 mediates antianoikis signals by both transcription-dependent and -independent mechanisms. Molecular and Cellular Biology, 33(13), 2574-85. https://doi.org/10.1128/MCB.01677-12
Jin L, et al. P90 RSK2 Mediates Antianoikis Signals By Both Transcription-dependent and -independent Mechanisms. Mol Cell Biol. 2013;33(13):2574-85. PubMed PMID: 23608533.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - p90 RSK2 mediates antianoikis signals by both transcription-dependent and -independent mechanisms. AU - Jin,Lingtao, AU - Li,Dan, AU - Lee,Jong Seok, AU - Elf,Shannon, AU - Alesi,Gina N, AU - Fan,Jun, AU - Kang,Hee-Bum, AU - Wang,Dongsheng, AU - Fu,Haian, AU - Taunton,Jack, AU - Boggon,Titus J, AU - Tucker,Meghan, AU - Gu,Ting-Lei, AU - Chen,Zhuo G, AU - Shin,Dong M, AU - Khuri,Fadlo R, AU - Kang,Sumin, Y1 - 2013/04/22/ PY - 2013/4/24/entrez PY - 2013/4/24/pubmed PY - 2013/8/28/medline SP - 2574 EP - 85 JF - Molecular and cellular biology JO - Mol. Cell. Biol. VL - 33 IS - 13 N2 - How invasive and metastatic tumor cells evade anoikis induction remains unclear. We found that knockdown of RSK2 sensitizes diverse cancer cells to anoikis induction, which is mediated through phosphorylation targets including apoptosis signal-regulating kinase 1 (ASK1) and cyclic AMP (cAMP) response element-binding protein (CREB). We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. Moreover, the RSK2→CREB signaling pathway provides antianoikis protection by regulating gene expression of protein effectors that are involved in cell death regulation, including the antiapoptotic factor protein tyrosine kinase 6 (PTK6) and the proapoptotic factor inhibitor-of-growth protein 3 (ING3). PTK6 overexpression or ING3 knockdown in addition to ASK1 knockdown further rescued the increased sensitivity to anoikis induction in RSK2 knockdown cells. These data together suggest that RSK2 functions as a signal integrator to provide antianoikis protection to cancer cells in both transcription-independent and -dependent manners, in part by signaling through ASK1 and CREB, and contributes to cancer cell invasion and tumor metastasis. SN - 1098-5549 UR - https://www.unboundmedicine.com/medline/citation/23608533/p90_RSK2_mediates_antianoikis_signals_by_both_transcription_dependent_and__independent_mechanisms_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=23608533 DB - PRIME DP - Unbound Medicine ER -