Abstract
Over the past decade, the involvement of tyrosine kinases in signal transduction pathways evoked by cytokines has been intensively investigated. Only relatively recently have the roles of serine/threonine kinases in cytokine-induced signal transduction and anti-apoptotic pathways been examined. Cytokine receptors without intrinsic kinase activity such as interleukin-3 (IL-3), granulocyte–macrophage colony-stimulating factor (GM-CSF) and the interferons were thought to transmit their regulatory signals primarily by the receptor-associated Jak family of tyrosine kinases. This family of tyrosine kinases activates STAT transcription factors, which subsequently transduced their signals into the nucleus to modulate gene expression. Cytokine receptors with intrinsic tyrosine kinase activity such as c-Kit were initially thought to transduce their signals independently of serine/threonine kinase cascades. Recently, both of these types of receptor signaling pathways have been shown to interact with serine/threonine kinase pathways as maximal activation of these tyrosine kinase regulated cascades involve serine/threonine phosphorylation modulated by, for example MAP kinases. A common intermediate pathway initiating from cytokine receptors is the Ras/Raf/MEK/ERK (MAPK) cascade, which can result in the phosphorylation and activation of additional downstream kinases and transcription factors such as p90Rsk, CREB, Elk and Egr-1. Serine/threonine phosphorylation is also involved in the regulation of the apoptosis-controlling Bcl-2 protein, as certain phosphorylation events induced by cytokines such as IL-3 are anti-apoptotic, whereas other phosphorylation events triggered by chemotherapeutic drugs such as Paclitaxel are associated with cell death. Serine/threonine phosphorylation is implicated in the etiology of certain human cancers as constitutive serine phosphorylation of STATs 1 and 3 is observed in chronic lymphocytic leukemia and can be inhibited by the chemotherapeutic drug fludarabine. Serine/threonine phosphorylation also plays a role in the etiology of immunodeficiencies. Activated STAT5 proteins are detected in reduced levels in lymphocytes recovered from HIV-infected individuals and immunocompromised mice. Serine/threonine phosphorylation may be an important target of certain chemotherapeutic drugs which recognize the activated proteins. This meeting report and mini-review will discuss the interactions of serine/threonine kinases with signal transduction and apoptotic molecules and how some of these pathways can be controlled by chemotherapeutic drugs.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Darnell JE Jr, Kerr IM, Stark GR . Jak-STAT pathways and transcription activation in response to IFNs and other extracellular signaling proteins Science 1994 264: 1415–1421
Ihle JN . The Janus protein tyrosine kinase family and its role in cytokine signaling Adv Immunol 1995 60: 1–35
Larner AC, David M, Feldman GM, Igarashi K, Hackett RH, Webb DS, Sweitzer SM, Petricoin EF III, Finbloom DS . Tyrosine phosphorylation of DNA binding proteins by multiple cytokines Science 1993 261: 1730–1733
Larner AC, Finbloom DS . Protein tyrosine phosphorylation as a mechanism which regulates cytokine activation of early response genes Biochim Biophys Acta 1995 1266: 278–287
Finbloom DS, Larner AC . Induction of early response genes by interferons, interleukins, and growth factors by the tyrosine phosphorylation of latent transcription factors. Implications for chronic inflammatory diseases Arthr Rheum 1995 38: 877–889
Finbloom DS, Larner AC . Regulation of the Jak/STAT signalling pathway Cell Signal 1995 7: 739–745
Kapur R, Everett ET, Uffmann J, McAndrews-Hill M, Cooper R, Ryder J, Vik T, Williams DA . Overexpression of human stem cell factor impairs melanocyte, mast cell, and thymocyte development: a role for receptor tyrosine kinase-mediated mitogen activated protein kinase activation in cell differentiation Blood 1997 90: 3018–3026
Kapur R, Majumdar M, Xiao X, McAndrews-Hill M, Schindler K, Williams DA . Signaling through the interaction of membrane-restricted stem cell factor and c-kit receptor tyrosine kinase: genetic evidence for a differential role in erythropoiesis Blood 1998 91: 879–889
Duronio V, Scheid MP, Ettinger S . Downstream signalling events regulated by phosphatidylinositol 3-kinase activity Cell Signal 1998 10: 233–239
Craddock BL, Welham MJ . Interleukin-3 induces association of the protein-tyrosine phosphatase SHP2 and phosphatidylinositol 3-kinase with a 100-kDa tyrosine-phosphorylated protein in hematopoietic cells J Biol Chem 1997 272: 29281–29289
Anderson SM, Burton EA, Koch BL . Phosphorylation of Cb1 following stimulation with interleukin-3 and its association with Grb2, Fyn and phosphatidylinositol 3-kinase J Biol Chem 1997 272: 739–745
Minshall C, Arkins S, Freund GG, Kelly KW . Requirement for phosphatidylinositol-3-kinase to protect hemopoietic progenitors against apoptosis depends upon the extracellular survival factor J Immunol 1996 156: 939–947
Kubota Y, Angelotti T, Niederfellner G, Herbst R, Ullrich A . Activation of phosphatidlyinositol 3-kinase is necessary for differentiation of FDC-P1 cells following stimulation of type III receptor tyrosine kinases Cell Growth Differ 1998 9: 247–256
Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD . Phosphoinositide 3-kinases: a conserved family of signal transducers Trends Biochem Sci 1997 22: 267–272
Pullen N, Thomas G . The modular phosphorylation and activation of p70S6K FEBS Lett 1997 410: 78–82
Downward J . Mechanisms and consequences of activation of protein kinase B/Akt Curr Opin Cell Biol 1998 10: 262–267
Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S . Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase Proc Natl Acad Sci USA 1998 95: 11211–11216
Scheid MP, Duronio V . Dissociation of cytokine-induced phosphorylation of Bad and activation of PKB/akt: involvement of MEK upstream of Bad phosphorylation Proc Natl Acad Sci USA 1998 95: 7439–7444
Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ . Serine phosphorylation of death agonist Bad in response to survival factor results in binding to 14-3-3 not Bcl-xL Cell 1996 87: 619–628
del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G . Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt Science 1997 278: 687–689
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME . Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery Cell 1997 91: 231–241
Scheid MP, Duronio V . Phosphatidylinositol 3-OH kinase activity is not required for activation of mitogen-activate protein kinase by cytokines J Biol Chem 1996 271: 18134–18139
Scheid MP, Schubert KM, Duronio V . Regulation of Bad phosphorylation and association with Bcl-xL by the MAPK/ERK kinase J Biol Chem 1999 274: 31108–31113
Scheid MP, Lauener RW, Duronio V . Role of phosphatidylinositol 3-OH-kinase activity in the inhibition of apoptosis in haemopoietic cells: phosphatidylinositol 3-OH-kinase inhibitors reveal a difference in signalling between interleukin-3 and granulocyte–macrophage colony-stimulating factor Biochem J 1995 312: 159–162
Craddock BL, Orchiston EA, Hinton HJ, Welham MJ . Dissociation of apoptosis from proliferation, protein kinase B activation, and Bad phosphorylation in interleukin-3-mediated phosphoinositide 3-kinase signaling J Biol Chem 1999 274: 10633–10640
Hinton HJ, Welham MJ . Cytokine-induced protein kinase B activation and Bad phosphorylation do not correlate with cell survival of hematopoietic cells J Immunol 1999 162: 7002–7009
Wennstrom S, Downward J . Role of phosphoinositide 3-kinase in activation of ras and mitogen-activated protein kinase by epidermal growth factor Mol Cell Biol 1999 19: 4279–4288
Sutor SL, Vroman BT, Armstrong EA, Abraham RT, Karnitz LM . A phosphatidylinositol 3-kinase-dependent pathway that differentially regulates c-Raf and A-Raf J Biol Chem 1999 274: 7002–7010
Damen JE, Liu L, Rosten P, Humphries RK, Jefferson AB, Majerus PW, Krystal G . The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase Proc Natl Acad Sci USA 1996 93: 1689–1693
Huber M, Helgason CD, Scheid MP, Duronio V, Humphries RK, Krystal G . Targeted disruption of SHIP leads to steel factor-induced degranulation of mast cells EMBO J 1998 17: 7311–7319
David M, Petricoin E, Benjamin C, Pine R, Weber MJ, Larner AC . Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through Stat proteins Science 1995 269: 1721–1723
Sakatsume M, Stancato LF, David M, Silvennoinen O, Saharinen P, Pierce J, Larner AC, Finbloom DS . Interferon gamma activation of Raf-1 is Jak1-dependent and p21 ras-independent J Biol Chem 1998 273: 3021–3026
Stancato LF, Sakatsume M, David M, Dent P, Dong F, Petricoin EF, Krolewski JJ, Silvennoinen O, Saharinen P, Pierce J, Marshall CJ, Sturgill T, Finbloom DS, Larner AC . Beta interferon and oncostatin M activate Raf-1 and mitogen-activated protein kinase through a JAK1-dependent pathway Mol Cell Biol 1997 17: 3833–3840
Wojnowski L, Zimmer AM, Beck TW, Hahn H, Bernal R, Rapp UR, Zimmer A . Endothelial apoptosis in Braf-deficient mice Nat Genet 1997 16: 293–297
Wojnowski L, Stancato LF, Zimmer AM, Hahn H, Beck TW, Larner AC, Rapp UR, Zimmer A . c-raf-1 protein kinase is essential for mouse development Mech Dev 1998 76: 141–149
Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, Jove R . Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein Science 1995 269: 81–83
Chaturvedi P, Reddy MV, Reddy EP . Src kinases and not JAKs activate STATs during IL-3 induced myeloid cell proliferation Oncogene 1998 16: 1749–1758
Jain N, Zhang T, Fong SL, Lim CP, Cao X . Repression of Stat3 activity by activation of mitogen-activated protein kinase (MAPK) Oncogene 1998 17: 3157–3167
Stancato LF, Yu CR, Petricoin EF III, Larner AC . Activation of Raf-1 by interferon gamma and oncostatin M requires expression of the Stat1 transcription factor J Biol Chem 1998 273: 18701–18704
McCubrey JA, Steelman LS, Hoyle PA, Blalock WL, Weinstein-Oppenheimer CR, Franklin RA, Cherwinski H, Bosch E, McMahon M . Differential abilities of activated Raf oncoproteins to abrogate cytokine dependency, prevent apoptosis and induce autocrine growth factor synthesis in human hematopoietic cells Leukemia 1998 12: 1903–1929
Mayo MW, Wang X-Y, Algate PA, Arana GF, Hoyle PE, Steelman LS, McCubrey JA . Synergy between AUUUA motif disruption and enhancer insertion results in autocrine transformation of interleukin-3-dependent hematopoietic cells Blood 1995 86: 3139–3150
Wang X-Y, McCubrey JA . Malignant transformation induced by cytokine genes: a comparison of the abilities of germline and mutated interleukin 3 genes to transform hematopoietic cells by transcriptional and post-transcriptional mechanisms Cell Growth Differ 1996 7: 487–500
Wang XY, McCubrey JA . Differential effects of retroviral long terminal repeats on interleukin-3 gene expression and autocrine transformation Leukemia 1997 11: 1711–1725
Blalock WL, Weinstein-Oppenheimer C, Chang F, Hoyle PE, Wang XY, Algate PA, Franklin RA, Oberhaus SM, Steelman LS, McCubrey JA . Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells, possible sites for intervention with anti-neoplastic drugs Leukemia 1999 13: 1109–1166
Pritchard CA, Bolin L, Slattery R, Murray RL, McMahon M . Post-natal lethality and neurological and gastrointestinal defects in mice with targeted disruption of the A-Raf protein kinase Curr Biol 1996 6: 614–617
Samuels ML, Weber MJ, Bishop JM, McMahon M . Conditional transformation of cells and rapid activation of the mitogen-activated protein kinase cascade by an estradiol-dependent human Raf-1 protein kinase Mol Cell Biol 1993 13: 6241–6252
Pritchard CA, Samuels ML, Bosch E, McMahon M . Conditionally oncogenic forms of the A-Raf and B-Raf protein kinases display different biological and biochemical properties in NIH-3T3 cells Mol Cell Biol 1995 15: 9430–9442
Lloyd AC, Obermuller F, Staddon S, Barth CF, McMahon M, Land H . Cooperating oncogenes converge to regulate cyclin/Cdk complexes Genes Dev 1997 11: 663–677
Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon M . Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip Mol Cell Biol 1997 17: 5598–5611
Yan M, Dai T, Deak JC, Kyriakis JM, Zon LI, Woodgett JR, Templeton DJ . Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1 Nature 1994 372: 798–800
Lin A, Minden A, Martinetto H, Claret FX, Lange-Carter C, Mercurio F, Johnson GL, Karin M . Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2 Science 1995 268: 286–290
Karin M, Minden A, Lin A, McMahon M, Lange-Carter C, Derijard B, Davis RJ, Johnson GL . Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK Science 1994 266: 1719–1723
Xu S, Robbins D, Frost J, Dang A, Lange-Carter C, Cobb MH . MEKK1 phosphorylates MEK1 and MEK2 but does not cause activation of mitogen-activated protein kinase Proc Natl Acad Sci USA 1995 92: 6808–6812
Johnson NL, Gardner AM, Diener KM, Lange-Carter CA, Gleavy J, Jarpe MB, Minden A, Karin M, Zon LI, Johnson GL . Signal transduction pathways regulated by mitogen-activated/extracellular response kinase kinase kinase induce cell death J Biol Chem 1996 271: 3229–3237
Zanke BW, Rubie EA, Winnett E, Chan J, Randall S, Parsons M, Boudreau K, McInnis M, Yan M, Templeton DJ, Woodgett JR . Mammalian mitogen-activated protein kinase pathways are regulated through formation of specific kinase-activator complexes J Biol Chem 1996 271: 29876–29881
Han J, Lee JD, Bibbs L, Ulevitch RJ . A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells Science 1994 265: 808–811
Meier R, Rous J, Cuenda A, Nebreda AR, Cohen P . Cellular stresses and cytokines activate multiple mitogen-activated-protein kinase kinase homologues in PC12 and KB cells Euro J Biochem 1996 236: 796–805
Hibi M, Lin A, Smeal T, Minden A, Karin M . Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain Genes Dev 1993 7: 2135–2148
Lange-Carter CA, Johnson GL . Ras-dependent growth factor regulation of MEK kinase in PC12 cells Science 1994 265: 1458–1461
Wang XZ, Ron D . Stress-induced phosphorylation and activation of CHOP (GADD153) by p38 MAP kinase Science 1996 272: 1347–1349
Williams JG, Roberts TM . Signal transduction pathways involving the Raf proto-oncogene Cancer Metast Rev 1994 13: 105–116
McIlroy J, Chen D, Wjasow C, Michaeli T, Backer JM . Specific activation of p85–p110 phosphatidylinositol 3′-kinase stimulates DNA synthesis by Ras- and p70 S6 kinase-dependent pathways Mol Cell Biol 1997 17: 248–255
Rodriguez-Viciana P, Marte BM, Warne PH, Downward J . Phosphatidylinositol 3′kinase: one of the effectors of Ras Phil Trans Roy Soc London Series B: Biol Sci 1996 351: 225–231
Edelmann HM, Kuhne C, Petritsch C, Ballou LM . Cell cycle regulation of p70 S6 kinase and p42/p44 mitogen-activated protein kinases in Swiss mouse 3T3 fibroblasts J Biol Chem 1996 271: 963–971
Blenis J, Grammer T . Evidence for MEK-independent pathways regulating the prolonged activation of the ERK-MAP kinases Oncogene 1997 14: 1635–1642
Lenormand P, McMahon M, Pouyssegur J . Oncogenic Raf-1 activates the p70 S6 kinase via a mitogen-activated protein kinase-independent pathway J Biol Chem 1996 271: 15762–15768
Gelfand EW, Ishizuka T, Oshiba A, Sakata N, Terada N, Johnson GL . Aggregation of the FcεRI on mast cells stimulates c-Jun amino-terminal kinase activity J Biol Chem 1996 271: 12762–12766
Calvo V, Wood M, Gjertson C, Vik T, Bierer BE . Activation of 70-kDa S6 kinase, induced by the cytokines interleukin-3 and erythropoietin and inhibited by rapamycin, is not an absolute requirement for cell proliferation Eur J Immunol 1994 24: 2664–2671
Price DJ, Grove JR, Calvo V, Avruch J, Bierer BE . Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase Science 1992 257: 973–977
Sugiyama H, Papst P, Gelfand EW, Terada N . p70 S6 kinase sensitivity to rapamycin is eliminated by amino acid substitution of Thr229 J Immunol 1996 157: 656–660
Terada N, Franklin RA, Lucas JJ, Blenis J, Gelfand EW . Failure of rapamycin to block proliferation once resting cells have entered the cell cycle despite inactivation of p70 S6 kinase J Biol Chem 1993 268: 12062–12068
Thomas G, Hall MN . Tor signalling and control of cell growth Curr Opin Cell Biol 1997 9: 782–787
Sigal NH, Dumont FJ . Cyclosporin A, FK-506, and rapamycin: pharmacologic probes of lymphocyte signal transduction Annu Rev Immunol 1992 10: 519–560
Zohn IM, Campbell SL, Khosravi-Far R, Rossman KL, Der CJ . Rho family proteins and Ras transformation: the RHOad less traveled gets congested Oncogene 1998 17: 1415–1438
Gorvel JP, Chang TC, Boretto J, Azuma T, Chavrier P . Differential properties of D4/LyGDI versus RhoGDI: phosphorylation and rho GTPase selectivity FEBS Lett 1998 422: 269–273
Roberts A, Kim C, Zhen L, Lowe J, Kapur R, Petryniak B, Spaetti A, Pollock J, Borneo J, Bradford GB, Atkinson SJ, Dinauer MC, Williams DA . Deficiency of the hematopoietic cell-specific Rho-family GTPase, Rac2, is characterized by multiple abnormalities in neutrophil function and impaired host defense Immunity 1999 10: 183–196
Reddy BS, Simi B, Patel N, Aliaga C, Rao CV . Effect of amount and types of dietary fat on intestinal bacterial 7 alpha-dehydroxylase and phosphatidylinositol-specific phospholipase C and colonic mucosal diacylglycerol kinase and PKC activities during stages of colon tumor promotion Cancer Res 1996 56: 2314–2320
Murray NR, Davidson LA, Chapkin RS, Gustafson WC, Schattenberg DG, Fields AP . Overexpression of protein kinase C bII induces colonic hyperproliferation and increased sensitivity to colon carcinogenesis J Cell Biol 1999 145: 699–711
Davidson LA, Lupton JR, Jiang YH, Chang WC, Aukema HM, Chapkin RS . Dietary fat and fiber alter rat colonic protein kinase C isozyme expression J Nutrit 1995 125: 49–56
Lafave LM, Kumarathasan P, Bird RP . Effect of dietary fat on colonic protein kinase C and induction of aberrant crypt foci Lipids 1994 29: 693–700
Mufson RA . The role of serine/threonine phosphorylation in hematopoietic cytokine receptor signal transduction FASEB J 1997 11: 37–44
Rao P, Kitamura T, Miyajima A, Mufson RA . Human IL-3 receptor signaling: rapid induction of phosphatidylcholine hydrolysis is independent of protein kinase C but dependent on tyrosine phosphorylation in transfected NIH 3T3 cells J Immunol 1995 154: 1664–1674
Rinaudo MS, Su K, Falk LA, Halder S, Mufson RA . Human interleukin-3 receptor modulates bcl-2 mRNA and protein levels through protein kinase C in TF-1 cells Blood 1995 86: 80–88
Mufson RA, Gubina E, Rinaudo M, Baxter G . A phosphatidylcholine phospholipase C inhibitor, D609, blocks interleukin-3 (IL-3)-induced bcl-2 expression but not c-myc expression in human IL-3-dependent cells Exp Cell Res 1998 240: 228–235
Gubina E, Rinaudo MS, Szallasi Z, Blumberg PM, Mufson RA . Overexpression of protein kinase C isoform epsilon but not delta in human interleukin-3-dependent cells suppresses apoptosis and induces bcl-2 expression Blood 1998 91: 823–829
Sakamoto KM, Mignacca RC, Gasson JC . Signal transduction by granulocyte–macrophage colony-stimulating factor and interleukin-3 receptors Recept Channels 1994 2: 175–181
Kwon EM, Sakamoto KM . The molecular mechanism of action of granulocyte–macrophage/colony-stimulating factor J Invest Med 1996 44: 442–446
Lee HJ, Mignacca RC, Sakamoto KM . Transcriptional activation of egr-1 by granulocyte–macrophage colony-stimulating factor but not interleukin 3 requires phosphorylation of cAMP response element-binding protein (CREB) on serine 133 J Biol Chem 1995 270: 15979–15983
Wong A, Sakamoto KM . Granulocyte–macrophage colony-stimulating factor induces the transcriptional activation of egr-1 through a protein kinase A-independent signaling pathway J Biol Chem 1995 270: 30271–30273
Watanabe S, Kubota H, Sakamoto KM, Arai K . Characterization of cis-acting sequences and trans-acting signals regulating early growth response 1 and c-fos promoters through the granulocyte–macrophage colony-stimulating factor receptor in BA/F3 cells Blood 1997 89: 1197–1206
Mignacca RC, Lee HJ, Kwon EM, Sakamoto KM . Mechanism of transcriptional activation of the immediate early gene Egr-1 in response to PIXY321 Blood 1996 88: 848–854
Sakamoto KM, Fraser JK, Lee HJ, Lehman E, Gasson JC . Granulocyte–macrophage colony-stimulating factor and interleukin-3 signaling pathways converge on the CREB-binding site in the human egr-1 promoter Mol Cell Biol 1994 14: 5975–5985
Frank DA, Mahajan S, Ritz J . Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling Nature Med 1999 5: 444–447
Gollob JA, Schnipper CP, Murphy EA, Ritz J, Frank DA . The functional synergy between IL-12 and IL-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of STAT serine phosphorylation J Immunol 1999 162: 4472–4481
Frank DA, Robertson MJ, Bonni A, Ritz J, Greenberg ME . Interleukin 2 signaling involves the phosphorylation of Stat proteins Proc Natl Acad Sci USA 1995 92: 7779–7783
Frank DA, Varticovski L . BCR/ABL leads to the constitutive activation of Stat proteins, shares an epitope with tyrosine phosphorylated Stats Leukemia 1996 10: 1724–1730
Carlesso N, Frank DA, Griffin JD . Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) protein in hematopoietic cells lines transformed by Bcr/AB1 J Exp Med 1996 183: 811–820
Karras JG, Wang Z, Huo L, Howard RG, Frank DA, Rothstein TL . Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in normal, self-renewing B-1 cells but only inducibly expressed in conventional B lymphocytes J Exp Med 1997 185: 1035–1042
Frank DA, Mahajan S, Ritz J . B lymphocytes from patients with chronic lympocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues J Clin Invest 1997 100: 3140–3148
Pott C, Hiddemann W . Purine analogs in the treatment of chronic lympocytic leukemia Leukemia 1997 11: S25–S28
Durbin JE, Hackenmiller R, Simon MC, Levy DE . Targeted disruption of mouse Stat1 gene results in compromised innate immunity to viral disease Cell 1996 84: 443–450
Simpson SJ, Shah S, Comiskey M, de Jong YP, Wang B, Mizoguchi E, Bhan AK, Terhorst C . T cell-mediated pathology in two models of experimental colitis depends predominantly on the interleukin 12/signal transducer and activator of transcription (Stat)-4 pathway, but is not conditional on interferon gamma expression by T cells J Exp Med 1998 187: 1225–1234
Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kihimoto T, Akira S . Targeted disruption of the mouse Stat3 gene leads to embryonic lethality Proc Natl Acad Sci USA 1997 94: 3801–3804
Takeda K, Kamanaka M, Tanaka T, Kishimoto T, Akira S . Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice J Immunol 1996 157: 3220–3222
Kaplan MH, Schindler U, Smiley ST, Grusby MJ . Stat6 is required for mediating responses to IL-4 and for development of Th2 cells Immunity 1996 4: 313–319
Feldman GM, Rosenthal LA, Liu X, Hayes MP, Wynshaw-Boris A, Leonard WJ, Hennighausen L, Finbloom DS . STAT5-deficient mice demonstrate in granulocyte–macrophage colony-stimulating factor-induce proliferation and gene expression Blood 1997 90: 1768–1776
Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle J . Stat 5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses Cell 1998 93: 841–850
Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, King KL, Sheehan KCF, Yin L, Pennica D, Johnson EM, Schreiber RD . Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses Cell 1998 93: 373–383
Parganas E, Wang D, Stravopodis D, Topham DJ, Marine J-C, Teglund S, Vanin EF, Bodner S, Colamonici OR, van Deurson JM, Grosveld G, Ihle JN . Jak2 is essential for signalling through a variety of cytokine receptors Cell 1998 93: 385–395
Thomis DC, Lee W, Berg LJ . T cells from Jak3-deficient mice have intact TCR, but increased apoptosis J Immunol 1997 159: 4708–4719
Sohn SJ, Forbush KA, Nguyen N, Witthuhn B, Nosaka T, Ihle JN, Perlmutter RM . Requirement for Jak3 in mature T cells: its role in regulation of T cell homeostasis J Immunol 1998 160: 2130–2138
Pericle F, Kirken RA, Bronte V, Sconocchia G, DaSilva L, Segal DM . Immunocompromised tumor-bearing mice show a selective loss of STAT5a/b expression in T and B lymphocytes J Immunol 1997 159: 2580–2585
Pericle F, Pinto LA, Hicks S, Kirken RA, Sconocchia G, Rusnak J, Dolan MJ, Shearer G, Segal DM . HIV-1 infection induces a selective reduction in STAT5 protein expression J Immunol 1998 160: 28–31
Yamashita H, Xu J, Erwin RA, Farrar WL, Kirken RA, Rui H . Differential control of the phosphorylation state of proline-juxtaposed serine residues Ser725 and Ser730 of Stata in prolactin-sensistive cells J Biol Chem 1998 273: 30218–30224
Kirken RA, Malabarba MG, Xu J, Liu X, Farrar WL, Hennighausen L, Larner AC, Grimley PM, Rui H . Prolactin stimulates serine/tyrosine phosphorylation and formation of heterocomplexes of multiple Stat5 isoforms in Nb2 lymphocytes J Biol Chem 1997 272: 14098–14103
Kirken RA, Malabarba MG, Xu J, DaSilva RA, Liu X, Hennighausen L, Rui H, Farrar WL . Two discrete regions of interleukin-2 (IL2) receptor beta independently mediate IL2 activation of a PD98059/rapamycin/wortmannin-insensitive Stat5a/b serine kinase J Biol Chem 1997 272: 15459–15465
Lu KP, Hanes SD, Hunter T . A human peptidyl-prolyl isomerase essential for the regulation of mitosis Nature 1996 380: 544–547
Shen M, Stukenberg PT, Kirschner MW, Lu KP . The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins Genes Dev 1998 12: 706–720
Lu P-J, Zhou XZ, Shen M, Lu KP . Function of WW domains as phosphoserine or phosphothreonine-binding modules Science 1999 283: 1325–1328
Ranganathan R, Lu KP, Hunter T, Noel JP . Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent Cell 1997 89: 875–886
Yaffe MB, Schutkowski M, Shen M, Zhou XZ, Stukenberg PT, Rafeld JU, Xu J, Kuang J, Kirschner MW, Fischer G, Cantley LC, Lu KP . Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism Science 1997 278: 1957–1960
Shen M, Vogt V, Haggblom C, Hunter T, Lu KP . Characterization and cell cycle regulation of related human telomeric proteins Pin2 and TRF1 suggests a role in mitosis Proc Natl Acad Sci USA 1997 94: 13618–13622
Blagosklonny MV, Giannakakou P, el-Deiry WS, Kingston DG, Higgs PI, Neckers L, Fojo T . Raf-1/bcl-2 phosphorylation: a step from microtubule damage to cell death Cancer Res 1997 57: 130–135
Wang HG, Rapp UR, Reed JC . Bcl-2 targets the protein kinase Raf-1 to mitochondria Cell 1996 87: 629–638
Thompson CB, Gajewski TF . Apoptosis meets signal transduction: elimination of a Bad influence Cell 1996 87: 589–592
Reed JC, Miyashita T, Takayama S, Wang HG, Sato T, Krajewski S, Aime-Sempe C, Brodrug S, Kitada S, Hanada M . BCL-2 family proteins: regulators of cell death involved in the pathogenesis of cancer and resistance to therapy J Cell Biochem 1996 60: 23–32
Ito T, Deng X, Carr B, May WS . Bcl-2 phosphorylation required for anti-apoptosis function J Biol Chem 1997 272: 11671–11673
Ruvolo PP, Deng X, Carr BK, May WS . A functional role for mitochondrial protein kinase C alpha in Bcl2 phosphorylation and suppression of apoptosis J Biol Chem 1998 273: 25436–25442
Deng X, Ito T, Carr B, Mumby M, May WS . Reversible phosphorylation of Bcl-2 following IL-3 or bryostatin is mediated by interaction of PP2A J Biol Chem 1998 271: 34157–34163
May WS, Tyler PG, Ito T, Armstrong DK, Qatsha KA, Davidson NE . Interleukin-3 and bryostatin-1 mediate hyperphosphorylation of BCL2 alpha in association with suppression of apoptosis J Biol Chem 1994 269: 26865–26870
Rodi DJ, Janes RW, Sanganee HJ, Holton RA, Wallace BA, Makowski L . Screening of a library of phage-displayed peptides identifies human bcl-2 as a taxol-binding protein J Mol Biol 1999 285: 197–203
Blagosklonny MV, Schulte T, Nguyen P, Trepel J, Neckers LM . Taxol-induced apoptsis and phosphorylation of the Bcl-2 protein involves c-Raf-1 and represents a novel c-Raf-1 signal transduction pathway Cancer Res 1996 56: 1851–1854
Blagosklonny MV, Chuman Y, Bergan RC, Fojo T . Mitogen-activated protein kinase pathway is dispensable for microtubule-active drug-induced Raf-1/Bcl-2 phosphorylation and apoptosis in leukemia cells Leukemia 1999 13: 1028–1036
Hu ZB, Minden MD, McCulloch EA . Phosphorylation of Bcl-2 after exposure of human leukemic cells to retinoic acid Blood 1998 92: 1768–1775
Haldar S, Jena N, Croce C . Inactivation of Bcl-2 by phosphorylation Proc Natl Acad Sci USA 1995 92: 4507–4511
Haldar S, Chintapilli J, Croce CM . Taxol induces bcl-2 phosphorylation and death of prostate cancer cells Cancer Res 1996 56: 1253–1255
Haldar S, Basu A, Croce CM . Bcl2 is the guardian of microtubule integrity Cancer Res 1997 57: 229–233
Haldar S, Basu A, Croce CM . Serine-70 is one of the critical sites for drug-induced Bcl2 phosphorylation in cancer cells Cancer Res 1998 58: 1609–1615
Basu A, Haldar S . Microtubule-damagin drugs triggered bcl2 phosphorylation-requirement of phosphorylation on both serine-70 and serine-87 residues of bcl2 protein Int J Oncol 1998 13: 659–664
Srivastava RK, Srivastava AR, Korsmeyer SJ, Nesterova M, Cho-Chung YS, Longo DL . Involvement of microtubules in the regulation of Bcl2 phosphorylation and apoptosis through cyclic AMP-dependent protein kinase Mol Cell Biol 1998 18: 3509–3517
Srivastava RK, Mi QS, Hardwick JM, Longo DL . Deletion of the loop region of Bcl-2 completely blocks paclitaxel-induced apoptosis Proc Natl Acad Sci USA 1999 96: 3775–3780
Acknowledgements
The meeting was organized by Dr Allan Mufson and occurred 30 and 31 March at the Georgetown Holiday Inn, Washington, DC, USA. JAM was supported in part by a grant from the National Institute of Health (R01 CA51025). We sincerely thank Ms Catherine Spruill for the outstanding artwork.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
McCubrey, J., May, W., Duronio, V. et al. Serine/threonine phosphorylation in cytokine signal transduction. Leukemia 14, 9–21 (2000). https://doi.org/10.1038/sj.leu.2401657
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2401657
Keywords
This article is cited by
-
Cytosolic DNA sensors in neurodegenerative diseases: from physiological defenders to pathological culprits
EMBO Molecular Medicine (2024)
-
Phosphorylation of CrkL S114 induced by common gamma chain cytokines and T-cell receptor signal transduction
Scientific Reports (2021)
-
Autism Spectrum Disorder: Signaling Pathways and Prospective Therapeutic Targets
Cellular and Molecular Neurobiology (2021)
-
miR profile in pagetic osteoclasts: from large-scale sequencing to gene expression study
Journal of Molecular Medicine (2021)
-
Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer
Investigational New Drugs (2018)