PMID- 16204634 OWN - NLM STAT- MEDLINE DCOM- 20060209 LR - 20211203 IS - 0741-5400 (Print) IS - 0741-5400 (Linking) VI - 78 IP - 6 DP - 2005 Dec TI - S6 kinase 2 potentiates interleukin-3-driven cell proliferation. PG - 1378-85 AB - Interleukin-3 (IL-3) mediates hematopoietic cell survival and proliferation via several signaling pathways such as the Janus kinase/signal transducer and activator of transcription pathway, mitogen-activated protein kinase (MAPK) pathway, and phosphoinositide-3 kinase (PI-3K) pathway. Mammalian target of rapamycin (mTOR) is one of the downstream targets of the PI-3K pathway, and it plays an important role in hematopoiesis and immune cell function. To better elucidate how mTOR mediates proliferation signals from IL-3, we assessed the role of S6 kinase 2 (S6K2), one of the downstream targets of mTOR, in IL-3 signaling. We show that S6K2 is activated by IL-3 in the IL-3-dependent Ba/F3 cell line and that this is mediated by mTOR and its upstream activator PI-3K but not by the MAPK kinase/extracellular signal-regulated kinase pathway. S6K2 is also activated in primary mouse bone marrow-derived mast cells upon IL-3 stimulation. Expression of a rapamycin-resistant form of S6K2, T388E, in Ba/F3 cells provides a proliferation advantage in the absence or presence of rapamycin, indicating that S6K2 can potentiate IL-3-mediated mitogenic signals. In cells expressing T388E, rapamycin still reduces proliferation at all doses of rapamycin, showing that mTOR targets other than S6K2 play an important role in IL-3-dependent proliferation. Cell-cycle analysis shows that T388E-expressing Ba/F3 cells enter S phase earlier than the control cells, indicating that the proliferation advantage may be mediated by a shortened G1 phase. This is the first indication that S6K2 plays a role in IL-3-dependent cell proliferation. FAU - Cruz, Rebecca AU - Cruz R AD - Department of Biological Sciences, California State University at Long Beach, 1250 Bellflower Blvd., Long Beach, CA 90840, USA. FAU - Hedden, Lee AU - Hedden L FAU - Boyer, Derek AU - Boyer D FAU - Kharas, Michael G AU - Kharas MG FAU - Fruman, David A AU - Fruman DA FAU - Lee-Fruman, Kay K AU - Lee-Fruman KK LA - eng GR - S06 GM063119/GM/NIGMS NIH HHS/United States GR - T32 CA009054/CA/NCI NIH HHS/United States GR - S06 GM063119-010004/GM/NIGMS NIH HHS/United States GR - R01 AI050831/AI/NIAID NIH HHS/United States GR - 1 S06 GM63119-01/GM/NIGMS NIH HHS/United States GR - AI50831/AI/NIAID NIH HHS/United States GR - T32-CA9054/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20051004 PL - England TA - J Leukoc Biol JT - Journal of leukocyte biology JID - 8405628 RN - 0 (Interleukin-3) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (ribosomal protein S6 kinase, 90kDa, polypeptide 3) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Bone Marrow Cells/drug effects/*enzymology/immunology MH - Cell Division/drug effects/immunology MH - Cell Line MH - Cell Proliferation/*drug effects MH - Cells, Cultured MH - Dose-Response Relationship, Drug MH - G1 Phase/drug effects/immunology MH - Humans MH - Interleukin-3/*metabolism/pharmacology MH - Mast Cells/drug effects/*enzymology/immunology MH - Mice MH - Phosphatidylinositol 3-Kinases/drug effects/metabolism MH - Protein Kinases/*metabolism MH - Ribosomal Protein S6 Kinases, 90-kDa/drug effects/genetics/*metabolism MH - S Phase/drug effects/immunology MH - Signal Transduction/drug effects/immunology MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases PMC - PMC2424256 MID - NIHMS29849 EDAT- 2005/10/06 09:00 MHDA- 2006/02/10 09:00 PMCR- 2008/06/11 CRDT- 2005/10/06 09:00 PHST- 2005/10/06 09:00 [pubmed] PHST- 2006/02/10 09:00 [medline] PHST- 2005/10/06 09:00 [entrez] PHST- 2008/06/11 00:00 [pmc-release] AID - jlb.0405225 [pii] AID - 10.1189/jlb.0405225 [doi] PST - ppublish SO - J Leukoc Biol. 2005 Dec;78(6):1378-85. doi: 10.1189/jlb.0405225. Epub 2005 Oct 4.