MEGAKARYOCYTE GROWTH AND DEVELOPMENT FACTOR AND INTERLEUKIN-3 INDUCE PATTERNS OF PROTEIN-TYROSINE PHOSPHORYLATION THAT CORRELATE WITH DOMINANT DIFFERENTIATION OVER PROLIFERATION OF MPL-TRANSFECTED 32D CELLS

被引:54
作者
MU, SX [1 ]
XIA, M [1 ]
ELLIOTT, G [1 ]
BOGENBERGER, J [1 ]
SWIFT, S [1 ]
BENNETT, L [1 ]
LAPPINGA, DL [1 ]
HECHT, R [1 ]
LEE, R [1 ]
SARIS, CJM [1 ]
机构
[1] AMGEN INC,AMGEN CTR,DEPT DEV BIOL,THOUSAND OAKS,CA 91320
关键词
D O I
10.1182/blood.V86.12.4532.bloodjournal86124532
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Recently, the ligand for c-mpl, a member of the family of cytokine receptors, was cloned and found to be a physiologic regulator of platelet homeostasis. We report that megakaryocyte growth and development factor (MGDF, thrombopoietin [TPO], c-mpl ligand) induces differentiation in a majority of mpl-transfected 32D cells, while interleukin (IL)-3 is exclusively mitogenic in this system. MGDF differentiation, as measured by decreased proliferation, changes in cellular morphology, increased adherence, and downregulation of very late antigen (VLA)-4, is dominant over IL-3 proliferation. MGDF induces tyrosine-phosphorylation of mpl, JAK2, SHC, SHPTP-1 (HCP, motheaten) and SHPTP-2 (Syp, PTP-1D) within 30 seconds of stimulation, as well as of vav and MAPK with slightly delayed kinetics. A fraction of mpl and JAK2 is preassociated, and the stoichiometry of this complex is unaltered by cytokine stimulation. After MGDF stimulation, we detect interactions among SHC, grb2, SHPTP-1, SHPTP-2, and the mpl/JAK2 complex. IL-3 induces phosphorylation of the above proteins with the exception of mpl and also causes weak JAK1 phosphorylation. Although similar in composition, the MGDF- and IL-3-induced complexes of signal transducers appear to be assembled in different configurations, especially with respect to SHPTP-2. Both MGDF and IL-3 induce tyrosine phosphorylation of STAT3 (APRF) and STATE (MGF), with MGDF favoring STAT3 while IL-3 predominantly causes STATE phosphorylation. In addition, some proteins become tyrosine-phosphorylated in response to MGDF only, suggesting that we may have detected differentiation-specific signal transducers. These include a number of high-molecular-weight proteins (140 to 200 kD) and one 28-kD protein that becomes tyrosine-phosphorylated only briefly. (C) 1995 by The American Society of Hematology.
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页码:4532 / 4543
页数:12
相关论文
共 76 条
[1]   MOLECULAR-CLONING OF APRF, A NOVEL IFN-STIMULATED GENE FACTOR-3 P91-RELATED TRANSCRIPTION FACTOR INVOLVED IN THE GP130-MEDIATED SIGNALING PATHWAY [J].
AKIRA, S ;
NISHIO, Y ;
INOUE, M ;
WANG, XJ ;
WEI, S ;
MATSUSAKA, T ;
YOSHIDA, K ;
SUDO, T ;
NARUTO, M ;
KISHIMOTO, T .
CELL, 1994, 77 (01) :63-71
[2]   CHARACTERIZATION OF ADHESIVE INTERACTIONS BETWEEN HUMAN ENDOTHELIAL-CELLS AND MEGAKARYOCYTES [J].
AVRAHAM, H ;
COWLEY, S ;
CHI, SY ;
JIANG, SX ;
GROOPMAN, JE .
JOURNAL OF CLINICAL INVESTIGATION, 1993, 91 (06) :2378-2384
[3]   INTERLEUKIN-3 SIGNALS THROUGH MULTIPLE ISOFORMS OF STAT5 [J].
AZAM, M ;
ERDJUMENTBROMAGE, H ;
KREIDER, BL ;
XIA, M ;
QUELLE, F ;
BASU, R ;
SARIS, C ;
TEMPST, P ;
IHLE, JN ;
SCHINDLER, C .
EMBO JOURNAL, 1995, 14 (07) :1402-1411
[4]   IDENTIFICATION AND CLONING OF A MEGAKARYOCYTE GROWTH AND DEVELOPMENT FACTOR THAT IS A LIGAND FOR THE CYTOKINE RECEPTOR MPL [J].
BARTLEY, TD ;
BOGENBERGER, J ;
HUNT, P ;
LI, YS ;
LU, HS ;
MARTIN, F ;
CHANG, MS ;
SAMAL, B ;
NICHOL, JL ;
SWIFT, S ;
JOHNSON, MJ ;
HSU, RY ;
PARKER, VP ;
SUGGS, S ;
SKRINE, JD ;
MEREWETHER, LA ;
CLOGSTON, C ;
HSU, E ;
HOKOM, MM ;
HORNKOHL, A ;
CHOI, E ;
PANGELINAN, M ;
SUN, Y ;
MAR, V ;
MCNINCH, J ;
SIMONET, L ;
JACOBSEN, F ;
XIE, C ;
SHUTTER, J ;
CHUTE, H ;
BASU, R ;
SELANDER, L ;
TROLLINGER, D ;
SIEU, L ;
PADILLA, D ;
TRAIL, G ;
ELLIOTT, G ;
IZUMI, R ;
COVEY, T ;
CROUSE, J ;
GARCIA, A ;
XU, W ;
DELCASTILLO, J ;
BIRON, J ;
COLE, S ;
HU, MCT ;
PACIFICI, R ;
PONTING, I ;
SARIS, C ;
WEN, D .
CELL, 1994, 77 (07) :1117-1124
[6]  
BENIT L, 1994, J VIROL, V68, P5270
[7]   CLONING AND CHARACTERIZATION OF THE HUMAN MEGAKARYOCYTE GROWTH AND DEVELOPMENT FACTOR (MGDF) GENE [J].
CHANG, MS ;
MCNINCH, J ;
BASU, R ;
SHUTTER, J ;
HSU, RY ;
PERKINS, C ;
MAR, V ;
SUGGS, S ;
WELCHER, A ;
LI, L ;
LU, H ;
BARTLEY, T ;
HUNT, P ;
MARTIN, F ;
SAMAL, B ;
BOGENBERGER, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (02) :511-514
[8]   RECOMBINANT HUMAN MEGAKARYOCYTE GROWTH AND DEVELOPMENT FACTOR (RHUMGDF), A LIGAND FOR C-MPL, PRODUCES FUNCTIONAL HUMAN PLATELETS IN-VITRO [J].
CHOI, ES ;
HOKOM, M ;
BARTLEY, T ;
LI, YS ;
OHASHI, H ;
KATO, T ;
NICHOL, JL ;
SKRINE, J ;
KNUDTEN, A ;
CHEN, J ;
HORNKOHL, A ;
GRAMPP, G ;
SLEEMAN, L ;
COLE, S ;
TRAIL, G ;
HUNT, P .
STEM CELLS, 1995, 13 (03) :317-322
[9]  
DAMEN J, 1992, BLOOD, V80, P1923
[10]  
DAMEN JE, 1993, BLOOD, V82, P2296