MAPKAP kinase

Stokoe, D., Engel, K., Campbell, D. G., Cohen, P., and Gaestel, M. (1992). Identification of MAPKAP kinase 2 as a major enzyme responsible for the phosphorylation of the small mammalian heat shock proteins. FEBS Lett. 313, 307—313. 

Conversely, the SAPK/JNK cascade, which is closely associated with apoptosis, is activated by sphingosine (Pyne et al, 1996). Exogenous sphingosine also activates caspase-7in a Bcl-x(L)-sensitive manner wha-eas caspase-8 was unaffected (Nava et al, 2000 Cuvillier et al, 2001). hi addition, sphingosine stimulates p38 MAPK in osteoblast-like cells (Kozawa et al, 2000) but not in oligodendrocytes where is produces lysis (Hida et al, 1999). p38 MAPK is up-stream of MAPKAP kinase-2 and the... 

Maulik, N., Yoshida, T., Zu, Y.L., Sato, M., Banerjee, A., and Das, D.K. 1998. Ischemic preconditioning triggers tyrosine kinase signaling A potential role for MAPKAP kinase 2. Am. J. Physiol. 275 H1857-H1864. 

Gel not shown Heat shock protein 27 Hsp27 Phosphorylation of Hsp27 at Thr-143 by PKG reduced the stimulatory effect of MAPKAP kinase 2-phosphorylated Hsp27 on actin polymerization (Butt et al., 2001)... 

Figure 11.5 Autoradiograms of 2D phosphoproteomics from wiidtype (WT), MAPKAP kinase 2 deficient (MK2 -/-) and MAPKAP kinase 5 deficient (MK5 -/-) mouse cardiac fibroblasts before and after stimulation with 100 pM arsenite.

LTC4 synthase. The mechanism by which 5-LO is trafficked to the nuclear membrane is controlled by the C2-like domain of 5-LO that binds two Ca " " ions which imparts high affinity for glycerophosphocholine lipids rich on the outer leaflet of either nuclear membrane [25]. 5-LO can be phosphorylated at S271 (MAPKAP kinase dependent) and S663 (ERK-1/2 dependent) to increase 5-LO activity and direct trafficking of 5-LO to the nucleoplasm. However, phosphorylation of S523, a protein kinase A-dependent process, inhibits 5-LO activity (see below). 

Alessi DR. The protein kinase C inhibitors RO 31 8220 and GF 109203X are equally potent inhibitors of MAPKAP kinase -lb (Rsk-2) and p70 S6 kinase. FEES Lett. 1997 402 121-123. 

Figure 8 CREB phosphorylation by hypoxia does not require Ca, PCK, RSK-2, MAPK, or p38. Cells were pretreated with various drugs or vehicle (0.1% dimethyl sulfoxide) as indicated. Cells were then exposed to either normoxia (C, 21% O2) or hypoxia (H, 5% O2) for 6 hr, and whole-cell lysates were immunoblotted with an antibody specific for Ser phospho-CREB. (a) Cells were preincubated for 40 min in serum-fi ee medium in the presence of Ca and vehicle (—) or in serum-iree medium formulated without Ca and supplemented with 1 mM EGTA-I-100 pM BAPTA-AM (-h). The medium was then replaced (minus drug or vehicle) and cells were exposed to either normoxia or hypoxia, (b) Cells were pretreated for 40 min in serum-free medium with either vehicle (—) or 20 pM chelerythrine chloride, an inhibitor of PKC (CHL -P), and exposed to either normoxia or hypoxia, (c) Cells were pretreated for 40 min in serum-fi ee medium with either vehicle (—) or 0.3 pM Ro 31-8220, an inhibitor of RSK and p70 S6 kinase (-P), and exposed to either normoxia or hypoxia, (d) Cells were pretreated for 40 min in serum-lree medium with either vehicle (—) or 50 pM PD098059, an inhibitor of MEKl and the downstream MAPKS (-P), and exposed to either normoxia or hypoxia, (e) Cells were pretreated for 1 hr in serum-fiee medium with either vehicle (—) or 10 nM rapamycin, an inhibitor of p70 S6 kinase (-P), and exposed to either normoxia or hypoxia, (f) Cells were pretreated for 1 hr in serum-fiee medium with either vehicle (—) or 20 pM SB203580, an inhibitor of p38a kinase and MAPKAP kinase (-P), and then exposed to either normoxia or hypoxia. In all of these experiments, hypoxia did not alter the total levels of CREB.

Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ. FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J 1996 15 4629 642. 

Rational Mutagenesis to Support Structure-Based Drug Design MAPKAP Kinase 2 as... 

MAPKAP kinase 2 (MK2) plays a key role in the production of pro-inflammatory cytokines such as TNF-a. MK2 is activated by the mitogen-activated protein (MAP) kinase p38 [1-3]. Activated MK2 phosphorylates a number of target proteins in immune cells resulting in cytokine production and cellular proliferation and activation. Mice lacking MK2 are healthy and fertile, but they fail to increase production of pro-inflammatory cytokines such as TNF-a, lL-6, and IFN-y [4] in response to stimuli such as lipopolysaccharide. MK2 knockout mice are resistant to the development of collagen-induced arthritis, a model for human rheumatoid arthritis [5]. The catalytic activity of MK2 is required to mount the pro-inflammatory response [6]. These and related studies have attracted attention to MK2 as a target for the design of therapeutic treatments for rheumatoid arthritis and other TNF-a-driven diseases. 

Stokoe D, Campbell DG, Nakielny S, Hidaka H, Leevers SJ, Marshall C, Cohen P MAPKAP kinase-2 a novel protein kinase activated by mitogen-activated protein kinase. EMBO J 1992, 11(11) 3985—3994. 

Kotlyarov A, Neininger A, Schubert C, Eckert R, Birchmeier C, Volk H, Gaestel M MAPKAP kinase 2 is essential for LPS-induced TNF-a biosynthesis. 

Hegen M, Gaestel M, Nickerson-Nutter CL, Lin L-L, Telbez J-B MAPKAP Kinase 2-Deficient Mice Are Resistant to Collagen-Induced Arthritis. J Immunol 2006, 177(3) 1913-1917. 

JR, Lippke JA Structure of Mitogen-activated Protein Kinase-activated Protein (MAPKAP) Kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear export. 2002, 277 37401—37405. 

Engel K, Kodyarov A, Gaestel M Leptomycin B-sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation. EMBO 1 1998, 17 3363— 3371. 

Ben-Levy R, Hooper S, Wilson R, Paterson HF, Marshall GJ Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. Curr Biol 1998, 8(19) 1049-1057. 

Ben-Levy R, Leighton lA, Doza YN, Attwood P, Mortice N, Marshall CJ, Cohen P Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2. EMBO J 1995, 14 5920-5930. 

Kurumbail RG, Pawlitz JL, Stegeman RA, Stallings WC, Shieh HS, Mourey RJ, Bolten SL, Broadus RM Crystalline structure of human MAPKAP kinase-2. WO 2003/076333 A2 2003, 135. 

MK2 (also termed MAP kinase-activated protein kinase 2, MAPKAP-K2) is activated by p38 MAP kinase a// (Kotlyarov et al, 2002 Roux and Blenis, 2004). MK2 plays a key role in the control of the production of certain cytokines, for example, tumor necrosis factor a. MK2 does so by phosphorylating proteins that bind specifically to the regulatory regions in the S untranslated regions (UTRs) of such mRNAs (Hitti et al, 2006). These regions contain AU-rich elements (AREs) to which proteins such as HnRNP A1 also bind. 

MAPKAP MAP-kinase-activated protein kinase NHE Na+/H+ antiporter... 

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