S6 kinase 2 potentiates interleukin-3-driven cell proliferation.
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.
Cruz
Rebecca
R
Department of Biological Sciences, California State University at Long Beach, 1250 Bellflower Blvd., Long Beach, CA 90840, USA.
Hedden
Lee
L
Boyer
Derek
D
Kharas
Michael G
MG
Fruman
David A
DA
Lee-Fruman
Kay K
KK
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism* / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D007377:Interleukin-3; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3