Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

J. Biol. Chem. 269 (2): 1249-1256

© 1994 by The American Society for Biochemistry and Molecular Biology, Inc.

Protein kinase C-mediated serine phosphorylation directly activates Raf-1 in murine hematopoietic cells.

M P Carroll, and W S May

ABSTRACT Back to Top

Abstract: We have previously found that Raf-1, which is activated by hematopoietic growth factors in association with phosphorylation, is required for hematopoietic cell proliferation. Recently, 12-O-tetradecanoylphorbol 13-acetate has been found to mediate Raf-1 phosphorylation, suggesting that protein kinase C (PKC) may be involved in the Raf-1 activation mechanism(s). Since PKC can be activated by hematopoietic growth factors, it was investigated as a potential "Raf-1 kinase-kinase." Results demonstrate that bryostatin 1, a pharmacologic activator of PKC, induces activation of Raf-1 in FDC-P1 cells. PKC inhibitors H7 and staurosporine block both bryostatin 1- and interleukin-3-mediated Raf-1 phosphorylation and FDC-P1 cell proliferation. Additionally, an antisense c-raf oligodeoxyribonucleotide specifically inhibits bryostatin 1-mediated proliferation, indicating a necessary role for Raf-1 in PKC signaling. Purified PKC can phosphorylate Raf-1 serine residues to high stoichiometry in vitro. Comparative phosphopeptide maps localize two PKC phosphorylation sites to Raf-1 phosphopeptides isolated from hematopoietic growth factor- or bryostatin 1-stimulated cells. The sites of PKC-mediated Raf-1 phosphorylation are deduced to be Ser497 and Ser619. Furthermore, PKC-mediated serine phosphorylation is sufficient to activate the enzymatic function of Raf-1 in vitro. These findings demonstrate that activated PKC can promote hematopoietic cell growth by regulating the enzymatic activity of Raf-1 through direct serine phosphorylation.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer.
M. Heger, R. F. van Golen, M. Broekgaarden, and M. C. Michel (2013)
Pharmacol. Rev. 66, 222-307
   Abstract »    Full Text »    PDF »
HIV-1 Infection Abrogates CD8+ T Cell Mitogen-Activated Protein Kinase Signaling Responses.
T. Q. Crawford, L. C. Ndhlovu, A. Tan, A. Carvidi, F. M. Hecht, E. Sinclair, and J. D. Barbour (2011)
J. Virol. 85, 12343-12350
   Abstract »    Full Text »    PDF »
Glucocorticoids promote survival of anti-inflammatory macrophages via stimulation of adenosine receptor A3.
K. Barczyk, J. Ehrchen, K. Tenbrock, M. Ahlmann, J. Kneidl, D. Viemann, and J. Roth (2010)
Blood 116, 446-455
   Abstract »    Full Text »    PDF »
Small G proteins exhibit pattern sensitivity in MAPK activation during the induction of memory and synaptic facilitation in Aplysia.
X. Ye, J. L. Shobe, S. K. Sharma, A. Marina, and T. J. Carew (2008)
PNAS 105, 20511-20516
   Abstract »    Full Text »    PDF »
Changes in Intracellular Ca2+ Levels Induced by Cytokines and P2 Agonists Differentially Modulate Proliferation or Commitment with Macrophage Differentiation in Murine Hematopoietic Cells.
E. J. Paredes-Gamero, C. M. M. P. Leon, R. Borojevic, M. E. M. Oshiro, and A. T. Ferreira (2008)
J. Biol. Chem. 283, 31909-31919
   Abstract »    Full Text »    PDF »
Characterization of Ser338 Phosphorylation for Raf-1 Activation.
M. Zang, J. Gong, L. Luo, J. Zhou, X. Xiang, W. Huang, Q. Huang, X. Luo, M. Olbrot, Y. Peng, et al. (2008)
J. Biol. Chem. 283, 31429-31437
   Abstract »    Full Text »    PDF »
Angiotensin II Activates Extracellular Signal-Regulated Kinase Independently of Receptor Tyrosine Kinases in Renal Smooth Muscle Cells: Implications for Blood Pressure Regulation.
C. S. Escano Jr., L. B. Keever, A. A. Gutweiler, and B. T. Andresen (2008)
J. Pharmacol. Exp. Ther. 324, 34-42
   Abstract »    Full Text »    PDF »
(S)-Armepavine inhibits human peripheral blood mononuclear cell activation by regulating Itk and PLC{gamma} activation in a PI-3K-dependent manner.
C.-P. Liu, Y.-C. Kuo, C.-C. Shen, M.-H. Wu, J.-F. Liao, Y.-L. Lin, C.-F. Chen, and W.-J. Tsai (2007)
J. Leukoc. Biol. 81, 1276-1286
   Abstract »    Full Text »    PDF »
Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo.
J. Liu, M. E. Fitzgerald, M. C. Berndt, C. W. Jackson, and T. K. Gartner (2006)
Blood 108, 2596-2603
   Abstract »    Full Text »    PDF »
Discovery of a Novel Shp2 Protein Tyrosine Phosphatase Inhibitor.
L. Chen, S.-S. Sung, M. L. R. Yip, H. R. Lawrence, Y. Ren, W. C. Guida, S. M. Sebti, N. J. Lawrence, and J. Wu (2006)
Mol. Pharmacol. 70, 562-570
   Abstract »    Full Text »    PDF »
Spatial and Functional Heterogeneity of Sphingolipid-rich Membrane Domains.
E. Kiyokawa, T. Baba, N. Otsuka, A. Makino, S. Ohno, and T. Kobayashi (2005)
J. Biol. Chem. 280, 24072-24084
   Abstract »    Full Text »    PDF »
Causal Protein-Signaling Networks Derived from Multiparameter Single-Cell Data.
K. Sachs, O. Perez, D. Pe'er, D. A. Lauffenburger, and G. P. Nolan (2005)
Science 308, 523-529
   Abstract »    Full Text »    PDF »
Erythropoietin regulation of Raf-1 and MEK: evidence for a Ras-independent mechanism.
C. Chen and A. J. Sytkowski (2004)
Blood 104, 73-80
   Abstract »    Full Text »    PDF »
Dynamic Changes in C-Raf Phosphorylation and 14-3-3 Protein Binding in Response to Growth Factor Stimulation: DIFFERENTIAL ROLES OF 14-3-3 PROTEIN BINDING SITES.
M. Hekman, S. Wiese, R. Metz, S. Albert, J. Troppmair, J. Nickel, M. Sendtner, and U. R. Rapp (2004)
J. Biol. Chem. 279, 14074-14086
   Abstract »    Full Text »    PDF »
Trihydrophobin 1 Is a New Negative Regulator of A-Raf Kinase.
W. Liu, X. Shen, Y. Yang, X. Yin, J. Xie, J. Yan, J. Jiang, W. Liu, H. Wang, M. Sun, et al. (2004)
J. Biol. Chem. 279, 10167-10175
   Abstract »    Full Text »    PDF »
12-O-Tetradecanoylphorbol-13-acetate May Both Potentiate and Decrease the Generation of Apoptosis by the Antileukemic Agent Arsenic Trioxide in Human Promonocytic Cells: REGULATION BY EXTRACELLULAR SIGNAL-REGULATED PROTEIN KINASES AND GLUTATHIONE.
C. Fernandez, A. M. Ramos, P. Sancho, D. Amran, E. de Blas, and P. Aller (2004)
J. Biol. Chem. 279, 3877-3884
   Abstract »    Full Text »    PDF »
Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling by inhibiting the PLC-gamma 1 and Itk activity.
M.-A. Kang, S.-Y. Yun, and J. Won (2003)
Blood 101, 3534-3542
   Abstract »    Full Text »    PDF »
EGF-Induced ERK Phosphorylation Independent of PKC Isozymes in Human Corneal Epithelial Cells.
K.-P. Xu, D. A. Dartt, and F.-S. X. Yu (2002)
Invest. Ophthalmol. Vis. Sci. 43, 3673-3679
   Abstract »    Full Text »    PDF »
Phosphorylation of 338SSYY341 Regulates Specific Interaction between Raf-1 and MEK1.
X. Xiang, M. Zang, C. A. Waelde, R. Wen, and Z. Luo (2002)
J. Biol. Chem. 277, 44996-45003
   Abstract »    Full Text »    PDF »
Cytosolic Retention of Phosphorylated Extracellular Signal-Regulated Kinase and a Rho-Associated Kinase-Mediated Signal Impair Expression of p21Cip1/Waf1 in Phorbol 12-Myristate-13- Acetate-Induced Apoptotic Cells.
J.-M. Lai, S. Wu, D.-Y. Huang, and Z.-F. Chang (2002)
Mol. Cell. Biol. 22, 7581-7592
   Abstract »    Full Text »    PDF »
Localization of Phospholipase D1 to Caveolin-enriched Membrane via Palmitoylation: Implications for Epidermal Growth Factor Signaling.
J. M. Han, Y. Kim, J. S. Lee, C. S. Lee, B. D. Lee, M. Ohba, T. Kuroki, P.-G. Suh, and S. H. Ryu (2002)
Mol. Biol. Cell 13, 3976-3988
   Abstract »    Full Text »    PDF »
SHIP Negatively Regulates IgE + Antigen-Induced IL-6 Production in Mast Cells by Inhibiting NF-{kappa}B Activity.
J. Kalesnikoff, N. Baur, M. Leitges, M. R. Hughes, J. E. Damen, M. Huber, and G. Krystal (2002)
J. Immunol. 168, 4737-4746
   Abstract »    Full Text »    PDF »
The PreS2 activator MHBst of hepatitis B virus activates c-raf-1/Erk2 signaling in transgenic mice.
E. Hildt, B. Munz, G. Saher, K. Reifenberg, and P. H. Hofschneider (2002)
EMBO J. 21, 525-535
   Abstract »    Full Text »    PDF »
ZAP-70-Independent Ca2+ Mobilization and Erk Activation in Jurkat T Cells in Response to T-Cell Antigen Receptor Ligation.
X. Shan, R. Balakir, G. Criado, J. S. Wood, M.-C. Seminario, J. Madrenas, and R. L. Wange (2001)
Mol. Cell. Biol. 21, 7137-7149
   Abstract »    Full Text »    PDF »
Erythropoietin Activates Two Distinct Signaling Pathways Required for the Initiation and the Elongation of c-myc.
C. Chen and A. J. Sytkowski (2001)
J. Biol. Chem. 276, 38518-38526
   Abstract »    Full Text »    PDF »
Alterations of the phosphoinositide 3-kinase and mitogen-activated protein kinase signaling pathways in the erythropoietin-independent Spi-1/PU.1 transgenic proerythroblasts.
S. Barnache, P. Mayeux, B. Payrastre, and F. Moreau-Gachelin (2001)
Blood 98, 2372-2381
   Abstract »    Full Text »    PDF »
Positive and negative regulation of Raf kinase activity and function by phosphorylation.
H. Chong, J. Lee, and K.-L. Guan (2001)
EMBO J. 20, 3716-3727
   Abstract »    Full Text »    PDF »
Pertussis toxin directly activates endothelial cell p42/p44 MAP kinases via a novel signaling pathway.
J. G. N. Garcia, P. Wang, F. Liu, M. B. Hershenson, T. Borbiev, and A. D. Verin (2001)
Am J Physiol Cell Physiol 280, C1233-C1241
   Abstract »    Full Text »    PDF »
Synergistic induction of apoptosis in human leukemia cells (U937) exposed to bryostatin 1 and the proteasome inhibitor lactacystin involves dysregulation of the PKC/MAPK cascade.
J. A. Vrana and S. Grant (2001)
Blood 97, 2105-2114
   Abstract »    Full Text »    PDF »
The Mechanism of Heat Shock Activation of ERK Mitogen-activated Protein Kinases in the Interleukin 3-dependent ProB Cell Line BaF3.
D. C. H. Ng and M. A. Bogoyevitch (2000)
J. Biol. Chem. 275, 40856-40866
   Abstract »    Full Text »    PDF »
Regulation of Bcl2 Phosphorylation and Potential Significance for Leukemic Cell Chemoresistance.
X. Deng, S. M. Kornblau, P. P. Ruvolo, and W. S. May Jr. (2000)
J Natl Cancer Inst Monographs 2000, 30-37
   Abstract »    Full Text »    PDF »
Tat Protein of Human Immunodeficiency Virus Type 1 Induces Interleukin-10 in Human Peripheral Blood Monocytes: Implication of Protein Kinase C-Dependent Pathway.
A. Badou, Y. Bennasser, M. Moreau, C. Leclerc, M. Benkirane, and E. Bahraoui (2000)
J. Virol. 74, 10551-10562
   Abstract »    Full Text »    PDF »
Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601.
B.-H. Zhang and K.-L. Guan (2000)
EMBO J. 19, 5429-5439
   Abstract »    Full Text »    PDF »
Growth Factor-Independent Proliferation of Erythroid Cells Infected with Friend Spleen Focus-Forming Virus Is Protein Kinase C Dependent but Does Not Require Ras-GTP.
K. W. Muszynski, D. Thompson, C. Hanson, R. Lyons, A. Spadaccini, and S. K. Ruscetti (2000)
J. Virol. 74, 8444-8451
   Abstract »    Full Text »    PDF »
The Recruitment of Raf-1 to Membranes Is Mediated by Direct Interaction with Phosphatidic Acid and Is Independent of Association with Ras.
M. A. Rizzo, K. Shome, S. C. Watkins, and G. Romero (2000)
J. Biol. Chem. 275, 23911-23918
   Abstract »    Full Text »    PDF »
Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases.
X. Deng, P. Ruvolo, B. Carr, and W. S. May Jr. (2000)
PNAS 97, 1578-1583
   Abstract »    Full Text »    PDF »
The SH2-Containing Inositol-5'-Phosphatase Enhances LFA-1-Mediated Cell Adhesion and Defines Two Signaling Pathways for LFA-1 Activation.
J. A. Rey-Ladino, M. Huber, L. Liu, J. E. Damen, G. Krystal, and F. Takei (1999)
J. Immunol. 162, 5792-5799
   Abstract »    Full Text »    PDF »
Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation.
C. S. Mason, C. J. Springer, R. G. Cooper, G. Superti-Furga, C. J. Marshall, and R. Marais (1999)
EMBO J. 18, 2137-2148
   Abstract »    Full Text »    PDF »
Activation of Stress-activated Protein Kinase/c-Jun NH2-terminal Kinase and p38 Kinase in Calphostin C-induced Apoptosis Requires Caspase-3-like Proteases but Is Dispensable for Cell Death.
I. Ozaki, E. Tani, H. Ikemoto, H. Kitagawa, and H. Fujikawa (1999)
J. Biol. Chem. 274, 5310-5317
   Abstract »    Full Text »    PDF »
Emergent Properties of Networks of Biological Signaling Pathways.
U. S. Bhalla and Ravi Iyengar (1999)
Science 283, 381-387
   Abstract »    Full Text »
Distinct Mechanisms Mediate the Initial and Sustained Phases of Integrin-mediated Activation of the Raf/MEK/Mitogen-activated Protein Kinase Cascade.
A. K. Howe and R. L. Juliano (1998)
J. Biol. Chem. 273, 27268-27274
   Abstract »    Full Text »    PDF »
A Functional Role for Mitochondrial Protein Kinase C{alpha} in Bcl2 Phosphorylation and Suppression of Apoptosis.
P. P. Ruvolo, X. Deng, B. K. Carr, and W. S. May (1998)
J. Biol. Chem. 273, 25436-25442
   Abstract »    Full Text »    PDF »
Ras Isoforms Vary in Their Ability to Activate Raf-1 and Phosphoinositide 3-Kinase.
J. Yan, S. Roy, A. Apolloni, A. Lane, and J. F. Hancock (1998)
J. Biol. Chem. 273, 24052-24056
   Abstract »    Full Text »    PDF »
Antimitogenic Effects of Trapidil In Coronary Artery Smooth Muscle Cells by Direct Activation of Protein Kinase A.
D. Bonisch, A.-A. Weber, M. Wittpoth, M. Osinski, and K. Schror (1998)
Mol. Pharmacol. 54, 241-248
   Abstract »    Full Text »    PDF »
14-3-3 Facilitates Ras-Dependent Raf-1 Activation In Vitro and In Vivo.
S. Roy, R. A. McPherson, A. Apolloni, J. Yan, A. Lane, J. Clyde-Smith, and J. F. Hancock (1998)
Mol. Cell. Biol. 18, 3947-3955
   Abstract »    Full Text »    PDF »
Signal Transduction and Signal Modulation by Cell Adhesion Receptors: The Role of Integrins, Cadherins, Immunoglobulin-Cell Adhesion Molecules, and Selectins.
A. E. Aplin, A. Howe, S. K. Alahari, and R. L. Juliano (1998)
Pharmacol. Rev. 50, 197-264
   Abstract »    Full Text »    PDF »
Differential translocation of protein kinase C isozymes by phorbol esters, EGF, and ANG II in rat liver WB cells.
J. A. Maloney, O. Tsygankova, A. Szot, L. Yang, Q. Li, and J. R. Williamson (1998)
Am J Physiol Cell Physiol 274, C974-C982
   Abstract »    Full Text »    PDF »
Signal Transduction Pathways Regulating Hematopoietic Differentiation.
T. E. Smithgall (1998)
Pharmacol. Rev. 50, 1-20
   Abstract »    Full Text »    PDF »
Activation of the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Pathway by Conventional, Novel, and Atypical Protein Kinase C Isotypes.
D. C. Schonwasser, R. M. Marais, C. J. Marshall, and P. J. Parker (1998)
Mol. Cell. Biol. 18, 790-798
   Abstract »    Full Text »    PDF »
A Role for Ca2+/Calmodulin-Dependent Protein Kinase II in the Mitogen-Activated Protein Kinase Signaling Cascade of Cultured Rat Aortic Vascular Smooth Muscle Cells.
S. T. Abraham, H. A. Benscoter, C. M. Schworer, and H. A. Singer (1997)
Circ. Res. 81, 575-584
   Abstract »    Full Text »
14-3-3 {zeta} Negatively Regulates Raf-1 Activity by Interactions with the Raf-1 Cysteine-rich Domain.
G. J. Clark, J. K. Drugan, K. L. Rossman, J. W. Carpenter, K. Rogers-Graham, H. Fu, C. J. Der, and S. L. Campbell (1997)
J. Biol. Chem. 272, 20990-20993
   Abstract »    Full Text »    PDF »
Sequential Modification of Serines 621 and 624 in the Raf-1 Carboxyl Terminus Produces Alterations in Its Electrophoretic Mobility.
A. F. Ferrier, M. Lee, W. B. Anderson, G. Benvenuto, D. K. Morrison, D. R. Lowy, and J. E. DeClue (1997)
J. Biol. Chem. 272, 2136-2142
   Abstract »    Full Text »    PDF »
Protein kinase C activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf.
Y. Ueda, S. Hirai, S. Osada, A. Suzuki, K. Mizuno, and S. Ohno (1996)
J. Biol. Chem. 271, 23512-23519
   Abstract »    Full Text »    PDF »
Heparin Inhibits Mitogen-activated Protein Kinase-dependent and -independent c-fos Induction in Mesangial Cells.
T. Miralem, A. Wang, C. I. Whiteside, and D. M. Templeton (1996)
J. Biol. Chem. 271, 17100-17106
   Abstract »    Full Text »    PDF »
1,25-Dihydroxyvitamin D3 Stimulates Expression and Translocation of Protein Kinase C{alpha} and C{delta} via a Nongenomic Mechanism and Rapidly Induces Phosphorylation of a 33-kDa Protein in Acute Promyelocytic NB4 Cells.
D. M. Berry, R. Antochi, M. Bhatia, and K. A. Meckling-Gill (1996)
J. Biol. Chem. 271, 16090-16096
   Abstract »    Full Text »    PDF »
Protein kinase C-zeta reverts v-raf transformation of NIH-3T3 cells..
A Kieser, T Seitz, H S Adler, P Coffer, E Kremmer, P Crespo, J S Gutkind, D W Henderson, J F Mushinski, W Kolch, et al. (1996)
Genes & Dev. 10, 1455-1466
   Abstract »    PDF »
Ceramide Inactivates Cellular Protein Kinase Calpha.
J. Y. Lee, Y. A. Hannun, and L. M. Obeid (1996)
J. Biol. Chem. 271, 13169-13174
   Abstract »    Full Text »    PDF »
Phorbol Ester Inhibits the Phosphorylation of the Retinoblastoma Protein without Suppressing Cyclin D-associated Kinase in Vascular Smooth Muscle Cells.
T. Sasaguri, A. Ishida, C. Kosaka, H. Nojima, and J. Ogata (1996)
J. Biol. Chem. 271, 8345-8351
   Abstract »    Full Text »    PDF »
Raf-1 Kinase Possesses Distinct Binding Domains for Phosphatidylserine and Phosphatidic Acid.
S. Ghosh, J. C. Strum, V. A. Sciorra, L. Daniel, and R. M. Bell (1996)
J. Biol. Chem. 271, 8472-8480
   Abstract »    Full Text »    PDF »
Hypertrophic Agonists Stimulate the Activities of the Protein Kinases c-Raf and A-Raf in Cultured Ventricular Myocytes.
M. A. Bogoyevitch, C. J. Marshall, and P. H. Sugden (1995)
J. Biol. Chem. 270, 26303-26310
   Abstract »    Full Text »    PDF »
Stratifin, a keratinocyte specific 14-3-3 protein, harbors a pleckstrin homology (PH) domain and enhances protein kinase C activity.
E. Dellambra, M. Patrone, B. Sparatore, A. Negri, F. Ceciliani, S. Bondanza, F. Molina, F. D. Cancedda, and M. De Luca (1995)
J. Cell Sci. 108, 3569-3579
   Abstract »    PDF »
A Composite Ets/Pit-1 Binding Site in the Prolactin Gene Can Mediate Transcriptional Responses to Multiple Signal Transduction Pathways.
P. W. Howard and R. A. Maurer (1995)
J. Biol. Chem. 270, 20930-20936
   Abstract »    Full Text »    PDF »
Distinct Pathways of G- and G-mediated Mitogen-activated Protein Kinase Activation.
B. E. Hawes, T. van Biesen, W. J. Koch, L. M. Luttrell, and R. J. Lefkowitz (1995)
J. Biol. Chem. 270, 17148-17153
   Abstract »    Full Text »    PDF »
Proteins of the 14-3-3 Family Associate with Raf and Contribute to Its Activation.
E. Freed, F. McCormick, and R. Ruggieri (1994)
Cold Spring Harb Symp Quant Biol 59, 187-193
   Abstract »    PDF »
The recruitment of Raf-1 to membranes is mediated by direct interaction with phosphatidic acid and is independent of association with Ras.
M. A Rizzo, K. Shome, S. C Watkins, and G. Romero (2000)
J. Biol. Chem.
   Abstract »
The mechanism of heat shock activation of ERK Mitogen-Activated Protein Kinases (ERK MAPKs) in the Interleukin 3-dependent cell line BaF3.
D. C.H. Ng and M. A. Bogoyevitch (2000)
J. Biol. Chem.
   Abstract »
Kinase Suppressor of Ras Signals through Thr269 of c-Raf-1.
H. R. Xing and R. Kolesnick (2001)
J. Biol. Chem. 276, 9733-9741
   Abstract »    Full Text »    PDF »
Inhibition of Anti-IgM-induced Translocation of Protein Kinase C beta I Inhibits ERK2 Activation and Increases Apoptosis.
M.-Y. Cao, F. Shinjo, S. Heinrichs, J.-W. Soh, J. Jongstra-Bilen, and J. Jongstra (2001)
J. Biol. Chem. 276, 24506-24510
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882