A Proline-Rich Sequence Unique to MEK1 and MEK2 Is Required for Raf Binding and Regulates MEK Function

Catling, Andrew D.; Schaeffer, Hans‐Joerg; Reuter, Christoph; Reddy, G. Ramakrishna; Weber, Michael J.

doi:10.1128/mcb.15.10.5214

Cited by 176 publications

(155 citation statements)

References 83 publications

(135 reference statements)

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“…While MKK1 shows a sustained activation upon serum stimulation of Dual Specificity Kinases N Dhanasekaran and EP Reddy ®broblasts such as Rat1 cells, MKK2 shows a transient activation. Although these di erences can be traced to an unique phosphorylation site present in MKK1, the physiological signi®cance of the closely related but di erentially regulated MKK1 and MKK2 pathways in cell proliferation and di erentiation is largely unknown at present (Catling et al, 1995).…”

Section: Map Kinase Kinase-1 and Map Kinase Kinase-2mentioning

confidence: 99%

Signaling by dual specificity kinases

1998

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Dual speci®city kinases that phosphorylate the Thr-and Tyr-residues within the TXY motif of MAP-kinases of play a central role in the regulation of various processes of cell growth. These dual speci®city kinases also known as MAP kinase kinases are constituents of the sequential kinase signaling modules. Seven distinct mammalian MAP kinases kinases have been identi®ed. Some of the unique signaling properties of these kinases are discussed here.

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Section: Map Kinase Kinase-1 and Map Kinase Kinase-2mentioning

confidence: 99%

Signaling by dual specificity kinases

1998

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“…Activation of p44 MAPK and p42 MAPK requires phosphorylation on both tyrosine and threonine residues by the dual-speci®c action of MAPK kinase (MAPKK), also known as MEK (MAPK/ERK) (LangeCarter et al, 1993;Cobb & Goldsmith, 1995). MAPKK is believed to be activated by Raf-1 which serves as an intermediate signalling molecule connecting the upstream PTKs and p21 ras and the downstream MAPK pathway (Catling et al, 1995;Marais et al, 1995). With the availability of a speci®c MAPKK inhibitor PD 098059 (Alessi et al, 1995;Dudley et al, 1995), the present study was conducted to determine the role of the MAPK signalling cascade in an in vitro model of allergic asthma.…”

Section: Introductionmentioning

confidence: 99%

Effects of mitogen‐activated protein kinase kinase inhibitor PD 098059 on antigen challenge of guinea‐pig airways in vitro

Tsang

Koh

Ting

et al. 1998

British J Pharmacology

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1 It has been shown that activation of protein tyrosine kinases is the earliest detectable signalling response to FceRI cross-linking on mast cell. Following tyrosine kinase activation, a family of mitogenactivated protein kinases (MAPKs) was found to be activated as well. The present study examined the role of MAPK signalling cascade in in vitro model of allergic asthma using a speci®c MAPK kinase inhibitor PD 098059. 2 Guinea-pigs were passively sensitized with IgG antibody raised against ovalbumin (OA). E ects of PD 098059 on OA-induced anaphylactic contraction of isolated bronchi and release of histamine and peptidoleukotrienes from chopped lung preparations were studied. 3 PD 098059 (10 ± 50 mM) produced only minor reduction of maximal OA-induced bronchial contraction. In contrast, the rate of relaxation of OA-induced bronchial contraction was markedly faster in the presence of PD 098059 than the vehicle control in a concentration-dependent manner. 4 These observations corroborate well with the inability of PD 098059 (5 ± 50 mM) to substantially block the OA-induced release of histamine and with marked inhibition of OA-induced release of peptidoleukotrienes from lung fragments in the presence of PD 098059. Exogenous arachidonic acidinduced release of peptidoleukotrienes from lung fragments was not blocked by PD 098059. 5 In immunoblotting study, we found that p42 MAPK was constitutively expressed in guinea-pig bronchi. However, treatment with OA, histamine or LTD 4 did not cause activation of p42 MAPK . These ®ndings together with the lack of inhibitory e ects of PD 098059 on bronchial contraction induced by histamine or LTD 4 suggest that histamine-and LTD 4 -induced bronchial contractions are not mediated by p42 MAPK activation. 6 Taken together, our ®ndings show that inhibition of MAPK signalling cascade by PD 098059 signi®cantly reduced the OA-triggered release of peptidoleukotrienes leading to rapid relaxation of anaphylactic bronchial contraction. On the other hand, p42 MAPK did not play a role in histamine-or LTD 4 -induced bronchial smooth muscle contraction suggesting that PD 098059 exerts its inhibitory e ects on OA-induced bronchial contraction primarily through inhibition of peptidoleukotrienes release from mast cells.

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“…All constructs were verified by nucleotide sequencing by using an ABI373 automatic sequencer. Ras (provided by K. L. Guan, University of Michigan Medical School, Ann Arbor, MI), RasV12, RasN17 (provided by L. Feig, Tufts University School of Medicine, Boston, MA), HA-B-Raf, pEBG-Raf1 (GST-Raf1), and GST-Ras (provided by K. L. Guan), and HA-MEK1, HA-MEK1⌬270-307 (provided by M. J. Weber, University of Virginia School of Medicine, Charlottesville, VA), have been described previously (Feig and Cooper, 1988;Catling et al, 1995;Robinson and Cobb, 1997;Sugimoto et al, 1997; Li et al, 2000). …”

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confidence: 99%

DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

Kelly

Rahmani

2005

MBoC

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Dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) is the human homologue of the Drosophila mnb (minibrain) gene. In Drosophila, mnb is involved in postembryonic neurogenesis. In human, DYRK1A maps within the Down syndrome critical region of chromosome 21 and is overexpressed in Down syndrome embryonic brain. Despite its potential involvement in the neurobiological alterations observed in Down syndrome patients, the biological functions of the serine/threonine kinase DYRK1A have not been identified yet. Here, we report that DYRK1A overexpression potentiates nerve growth factor (NGF)-mediated PC12 neuronal differentiation by up-regulating the Ras/MAP kinase signaling pathway independently of its kinase activity. Furthermore, we show that DYRK1A prolongs the kinetics of ERK activation by interacting with Ras, B-Raf, and MEK1 to facilitate the formation of a Ras/B-Raf/MEK1 multiprotein complex. These data indicate that DYRK1A may play a critical role in Ras-dependent transducing signals that are required for promoting or maintaining neuronal differentiation and suggest that overexpression of DYRK1A may contribute to the neurological abnormalities observed in Down syndrome patients. INTRODUCTIONMinibrain (mnb)/dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) gene is a member of a growing family of protein kinases called DYRK. In Drosophila, mnb seems to play an essential role during postembryonic neurogenesis. Mutant flies are characterized by a marked reduction in size of the adult optic lobes and the central brain hemispheres. This is caused by the abnormal spacing of neuroblasts and a reduction in the production of neuronal progeny (Tejedor et al., 1995). At least seven closely related homologous mammalian kinases in the DYRK family have since been isolated (Guimera et al., 1996(Guimera et al., , 1999Shindoh et al., 1996;Song et al., 1996Song et al., , 1997Raich et al., 2003). The DYRK family possesses serine and threonine phosphorylation activity as well as autophosphorylation activity on tyrosine residues (Kentrup et al., 1996;Becker et al., 1998;Becker and Joost, 1999;Himpel et al., 2000). Their kinase activity is dependent on the YXY motif in the activation loop of the catalytic domain, which is located at the same position as the characteristic TXY motif of the mitogen-activated protein kinases (MAPKs), suggesting an activation mechanism similar to that of the MAPK (Himpel et al., 2000). Closely related enzymes in lower eukaryotes also have been isolated, including Yak1p in Saccharomyces cerevisiae (Garrett and Broach, 1989), Pom1p in Schizosaccharomyces pombe (Bahler and Pringle, 1998), and YakA in Dictyostelium discoideum (Van Es et al., 2001). Although not much is known about their cellular functions, they all seem to be involved in the regulation of the cell growth and/or development.In the DYRK family, DYRK1A has been the best characterized to date. The human Dyrk1A gene maps to the 21q22.2 region of chromosome 21, in the Down syndrome critical region (Rah...

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A Proline-Rich Sequence Unique to MEK1 and MEK2 Is Required for Raf Binding and Regulates MEK Function

Cited by 176 publications

References 83 publications

Signaling by dual specificity kinases

Signaling by dual specificity kinases

Effects of mitogen‐activated protein kinase kinase inhibitor PD 098059 on antigen challenge of guinea‐pig airways in vitro

DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

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