Activation of stress‐activated protein kinase‐3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38)

Stress‐activated protein kinase‐3 (SAPK3), a recently described MAP kinase family member with a widespread tissue distribution, was transfected into several mammalian cell lines and shown to be activated in response to cellular stresses, interleukin‐1 (IL‐1) and tumour necrosis factor (TNF) in a similar manner to SAPK1 (also termed JNK) and SAPK2 (also termed p38, RK, CSBP and Mxi2). SAPK3 and SAPK2 were activated at similar rates in vitro by SAPKK3 (also termed MKK6), and SAPKK3 was the only activator of SAPK3 that was induced when KB or 293 cells were exposed to cellular stresses or stimulated with IL‐1 or TNF. Co‐transfection with SAPKK3 induced SAPK3 activity and greatly enhanced activation in response to osmotic shock. These experiments indicate that SAPKK3 mediates the activation of SAPK3 in several mammalian cells. SAPK3 and SAPK2 phosphorylated a number of proteins at similar rates, including the transcription factors ATF2, Elk‐1 and SAP1, but SAPK3 was far less effective than SAPK2 in activating MAPKAP kinase‐2 and MAPKAP kinase‐3. Unlike SAPK2, SAPK3 was not inhibited by the drug SB 203580. SAPK3 phosphorylated ATF2 at Thr69, Thr71 and Ser90, the same residues phosphorylated by SAPK1, whereas SAPK2 only phosphorylated Thr69 and Thr71. Our results suggest that cellular functions previously attributed to SAPK1 and/or SAPK2 may be mediated by SAPK3.

[1]  Philip R. Cohen,et al.  FGF and stress regulate CREB and ATF‐1 via a pathway involving p38 MAP kinase and MAPKAP kinase‐2. , 1996, The EMBO journal.

[2]  P. Cohen,et al.  The activation of distinct mitogen-activated protein kinase cascades is required for the stimulation of 2-deoxyglucose uptake by interleukin-1 and insulin-like growth factor-1 in KB cells. , 1995, The Biochemical journal.

[3]  H. Johnson,et al.  A comparison of 'traditional' and multimedia information systems development practices , 2003, Inf. Softw. Technol..

[4]  A. Ashworth,et al.  An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1 , 1995, Science.

[5]  J. Woodgett,et al.  The stress-activated protein kinase subfamily of c-Jun kinases , 1994, Nature.

[6]  James R. Woodgett,et al.  Phosphorylation of c-jun mediated by MAP kinases , 1991, Nature.

[7]  K. Irie,et al.  A Novel Kinase Cascade Mediated by Mitogen-activated Protein Kinase Kinase 6 and MKK3* , 1996, The Journal of Biological Chemistry.

[8]  B. Dérijard,et al.  Transcription factor ATF2 regulation by the JNK signal transduction pathway , 1995, Science.

[9]  S. Hirai,et al.  Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK. , 1996, Oncogene.

[10]  Xiaozhong Wang,et al.  Stress-Induced Phosphorylation and Activation of the Transcription Factor CHOP (GADD153) by p38 MAP Kinase , 1996, Science.

[11]  P. Cohen,et al.  Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress‐ and cytokine‐stimulated monocytes and epithelial cells. , 1996, The EMBO journal.

[12]  P. Cohen,et al.  MAPKAP kinase‐2; a novel protein kinase activated by mitogen‐activated protein kinase. , 1992, The EMBO journal.

[13]  A. Sharrocks,et al.  Integration of MAP kinase signal transduction pathways at the serum response element. , 1995, Science.

[14]  Jerry L. Adams,et al.  A protein kinase involved in the regulation of inflammatory cytokine biosynthesis , 1994, Nature.

[15]  P. Cohen,et al.  Mechanism of activation of protein kinase B by insulin and IGF‐1. , 1996, The EMBO journal.

[16]  R. Treisman,et al.  The p38 and ERK MAP kinase pathways cooperate to activate Ternary Complex Factors and c‐fos transcription in response to UV light. , 1996, The EMBO journal.

[17]  R. Brent,et al.  Mxi2, a mitogen-activated protein kinase that recognizes and phosphorylates Max protein. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[18]  N. Jones,et al.  ATF‐2 contains a phosphorylation‐dependent transcriptional activation domain. , 1995, The EMBO journal.

[19]  H. Kawasaki,et al.  Activation of Protein Kinase Cascades by Osmotic Shock (*) , 1995, The Journal of Biological Chemistry.

[20]  Philip R. Cohen,et al.  PD 098059 Is a Specific Inhibitor of the Activation of Mitogen-activated Protein Kinase Kinase in Vitro and in Vivo(*) , 1995, The Journal of Biological Chemistry.

[21]  M. Cobb,et al.  Cloning of rat MEK kinase 1 cDNA reveals an endogenous membrane-associated 195-kDa protein with a large regulatory domain. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Karin,et al.  Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. , 1993, Genes & development.

[23]  G L Johnson,et al.  Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. , 1994, Science.

[24]  M. J. Barratt,et al.  p38/RK is essential for stress-induced nuclear responses: JNK/SAPKs and c-Jun/ATF-2 phosphorylation are insufficient , 1996, Current Biology.

[25]  A. Guimond,et al.  Characterization of 45-kDa/54-kDa HSP27 kinase, a stress-sensitive kinase which may activate the phosphorylation-dependent protective function of mammalian 27-kDa heat-shock protein HSP27. , 1995, European journal of biochemistry.

[26]  Jiahuai Han,et al.  Characterization of the Structure and Function of a Novel MAP Kinase Kinase (MKK6) (*) , 1996, The Journal of Biological Chemistry.

[27]  Philip R. Cohen,et al.  A comparison of the substrate specificity of MAPKAP kinase‐2 and MAPKAP kinase‐3 and their activation by cytokines and cellular stress , 1996, FEBS letters.

[28]  L. Zon,et al.  The Mixed Lineage Kinase SPRK Phosphorylates and Activates the Stress-activated Protein Kinase Activator, SEK-1* , 1996, The Journal of Biological Chemistry.

[29]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[30]  Stanley T. Rolfe,et al.  A Comparison of the J -lntegral and CTOD Parameters for Short Crack Specimen Testing , 1991 .

[31]  M. Goedert,et al.  SAP kinase‐3, a new member of the family of mammalian stress‐activated protein kinases , 1996, FEBS letters.

[32]  R. Hipskind,et al.  Protein synthesis inhibitors reveal differential regulation of mitogen-activated protein kinase and stress-activated protein kinase pathways that converge on Elk-1 , 1995, Molecular and cellular biology.

[33]  Michel Morange,et al.  A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins , 1994, Cell.

[34]  Wei Guo,et al.  Characterization of the Structure and Function of a New Mitogen-activated Protein Kinase (p38β)* , 1996, The Journal of Biological Chemistry.

[35]  J. Blank,et al.  Molecular Cloning of Mitogen-activated Protein/ERK Kinase Kinases (MEKK) 2 and 3 , 1996, The Journal of Biological Chemistry.

[36]  J. Landry,et al.  Modulation of cellular thermoresistance and actin filament stability accompanies phosphorylation-induced changes in the oligomeric structure of heat shock protein 27 , 1995, Molecular and cellular biology.

[37]  A. Ashworth,et al.  Assay and expression of mitogen-activated protein kinase, MAP kinase kinase, and Raf. , 1995, Methods in enzymology.

[38]  K. Wagner,et al.  Mechanism of activation of protein kinase I from rabbit skeletal muscle. Investigation with agarose-immobilized cAMP derivatives. , 1978, European journal of biochemistry.

[39]  P. Cohen,et al.  Activation of the MAP kinase homologue RK requires the phosphorylation of Thr‐180 and Tyr‐182 and both residues are phosphorylated in chemically stressed KB cells , 1995, FEBS letters.

[40]  M. Karin,et al.  Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. , 1995, Science.

[41]  W. Fiers,et al.  The p38/RK mitogen‐activated protein kinase pathway regulates interleukin‐6 synthesis response to tumor necrosis factor. , 1996, The EMBO journal.

[42]  M. Karin,et al.  Induction of c‐fos expression through JNK‐mediated TCF/Elk‐1 phosphorylation. , 1995, The EMBO journal.

[43]  Philip R. Cohen,et al.  The substrate specificity and structure of mitogen-activated protein (MAP) kinase-activated protein kinase-2. , 1993, The Biochemical journal.

[44]  Olive Lloyd-Baker.  IDENTIFICATION OF NOVEL , 1964 .

[45]  John C. Lee,et al.  Identification of Mitogen-activated Protein (MAP) Kinase-activated Protein Kinase-3, a Novel Substrate of CSBP p38 MAP Kinase (*) , 1996, The Journal of Biological Chemistry.

[46]  M. Karin,et al.  JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain , 1994, Cell.

[47]  L. Zon,et al.  Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun , 1994, Nature.

[48]  Philip R. Cohen,et al.  SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin‐1 , 1995, FEBS letters.

[49]  J. Hsuan,et al.  Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of hsp27 , 1994, Cell.

[50]  L. Zon,et al.  Novel members of the mitogen-activated protein kinase activator family in Xenopus laevis , 1993, Molecular and cellular biology.

[51]  David Stokoe,et al.  Identification of MAPKAP kinase 2 as a major enzyme responsible for the phosphorylation of the small mammalian heat shock proteins , 1992, FEBS letters.

[52]  John C. Lee,et al.  Role for p38 Mitogen-activated Protein Kinase in Platelet Aggregation Caused by Collagen or a Thromboxane Analogue (*) , 1996, The Journal of Biological Chemistry.

[53]  D. Pappin,et al.  Activation of MEK‐1 and SEK‐1 by Tpl‐2 proto‐oncoprotein, a novel MAP kinase kinase kinase. , 1996, The EMBO journal.

[54]  L. Zon,et al.  Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1 , 1994, Nature.

[55]  R. Davis,et al.  MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway , 1996, Molecular and cellular biology.

[56]  M. Greenberg,et al.  Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB , 1994, Cell.

[57]  Jiahuai Han,et al.  Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms , 1995, Science.

[58]  A. Ullrich,et al.  ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[59]  L Bibbs,et al.  A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. , 1994, Science.

[60]  D. Young,et al.  Cloning and Characterization of MEK6, a Novel Member of the Mitogen-activated Protein Kinase Kinase Cascade (*) , 1996, The Journal of Biological Chemistry.

[61]  Philip R. Cohen,et al.  Cellular stresses and cytokines activate multiple mitogen-activated-protein kinase kinase homologues in PC12 and KB cells. , 1996, European journal of biochemistry.

[62]  S. Elledge,et al.  Protein phosphatase 1 interacts with p53BP2, a protein which binds to the tumour suppressor p53 , 1995, FEBS letters.