Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1999-12-27
2002-10-15
Mertz, Prema (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C536S023200, C536S024300, C536S024310, C435S069100, C435S071100, C435S071200, C435S194000, C435S471000, C435S320100, C435S325000, C435S252300, C435S254110
Reexamination Certificate
active
06465618
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel MAPK kinase derived from a vertebrate and a DNA coding for the same. More particularly, the present invention is concerned with a MAPK kinase which is activated by a stimulus induced by TNF-&agr; and/or by a stimulation of Fas antigen, and which in turn activates SAPK/JNK, but does not activate p38. Also, the present invention is concerned with a DNA coding for the above-mentioned MAPK kinase. By the use of the MAPK kinase and the DNA coding for the same, it has become possible to provide a method for screening a novel substance which can be used for treating or preventing diseases resulting from an excess activation or inhibition of a MAP kinase cascade, and also to provide a diagnostic reagent for such diseases. The present invention is also concerned with a replicable recombinant DNA which comprises a replicable expression vector and, operably inserted therein, the above-mentioned DNA; a cell of a microorganism or cell culture, which is transformed with the above-mentioned replicable recombinant DNA; a polypeptide of a dominant negative form of the above-mentioned MAPK kinase and a DNA coding for the same; and an antibody capable of binding specifically to the above-mentioned MAPK kinase.
2. Prior Art
MAP (mitogen-activated protein) kinase (MAPK) was first discovered in the late 1980's as a serine/threonine kinase (Ser/Thr kinase; i.e., an enzyme capable of phosphorylating serine or threonine residues in a protein) which is activated by stimuli, such as insulin {Sturgill, T. W. et al.,
Biochim. Biophys. Acta,
1092: 350-357 (1991)}, various cell growth factors and tumor promoters {Nishida, E. et al.,
Int. Rev. Cytol.,
138: 211-238 (1992)}. Studies over the past 10 years revealed that the MAP kinase is a major functional unit of an intracellular signal transduction system which mediates cell determination and functional regulation of eukaryotic cells in response to extracellular stimuli {Nishida, E. et al.,
Trends Biochem. Sci.,
18: 128-131 (1993); Marshall, C. J.,
Curr. Opin. Genet. Dev.,
4: 82-89 (1994); and Cobb, M. H. et al.,
J. Biol. Chem.,
270: 14843-14846 (1995)}. Particularly, an important achievement in the field of cell biology of the 1990's is an elucidation of a signal transduction pathway which starts from a cell growth factor receptor having tyrosine kinase activity, through an adapter molecule composed of SH2 (Src homology 2) and SH3 (Src homology 3), Ras (an oncogene product which is a GTP-binding protein) and Raf-1 (an oncogene product which is a serine/threonine kinase), and leading to the MAP kinase. The studies revealed that this signal transduction pathway is a central pathway responsible for determining cell proliferation, cell differentiation, and cell development of higher eucaryotic organisms.
A signal transduction molecule is converted into an activated form (switched “on”) by a signal in the upstream of a signal transduction pathway, and the activated molecule returns to an inactive form (switched “off”) after transducing the signal to the downstream thereof. The regulatory mechanism for switching on/off the MAP kinase has an interesting feature. That is, phosphorylation of T and Y in the TEY (Thr-Glu-Tyr in 3-letter abbreviation) sequence located in the boundary region between the kinase subdomains VII and VIII is required for activating the MAP kinase. An enzyme called MAPK kinase (MAPKK) or MAPK/ERK kinase (MEK) was identified as an enzyme which catalyzes the phosphorylation (that is, activation) of these amino acid residues. MAPK kinase is a dual specificity kinase which is capable of phosphorylating both serine/threonine residue and tyrosine residue.
For activating a MAPK kinase, it is necessary to phosphorylate two serine and/or threonine residues (i.e., two serine residues, two threonine residues, or one serine residue and one threonine residue) located in the boundary region between the kinase subdomains VII and VIII, and a serine/threonine kinase responsible for this phosphorylation is designated MAPKK kinase (MAPKKK). The above-mentioned Raf-1 is one example of MAPKK kinase, and the following cascade reaction:
Ras→Raf-1 (i.e., MAPKKK)→MAPKK→MAPK,
is one of the major signal transduction pathways. The cascade reaction consisting of three kinase molecules,
MAPKKK→MAPKK→MAPK,
is called a MAP kinase signal cascade.
The above-mentioned signal transduction system,
Raf-1/MAPKKK→MAPKK→MAPK,
is the first identified MAP kinase signal cascade and, therefore, this system is frequently called “classical MAP kinase signal pathway”. Later studies revealed the existence of various kinases which are similar to the classical MAP kinase. One example of such a kinase is stress-activated protein kinase (SAPK). This enzyme has been identified as a kinase which is activated in response to a stimulation of a cell by chemical stresses (such as protein synthesis inhibitor) or physical stresses (such as heat shock or change in osmotic pressure) {Kyriakis, J. M.,
Nature,
369: 156-160 (1994)}. SAPK was later found to be identical to c-Jun N-terminal kinase (JNK), which is a kinase identified independently from and contemporaneously with SAPK, and phosphorylates the N-terminus of transcription factor Jun to increase the transcription activity thereof {Derijard, B.,
Cell,
76: 1025-1037 (1994)} (hereinafter, SAPK and JNK are frequently referred to as “SAPK/JNK”). SAPK/JNK has homology to the classical MAP kinase, and a sequence corresponding to the TEY sequence necessary for the activation of the classical MAP kinase is TPY (Thr-Pro-Tyr) in SAPK/JNK. SAPK/JNK is similar to the classical MAP kinase in that the Thr and Tyr residues in the above-mentioned sequence are phosphorylated by a sole MAPK kinase in the upstream thereof, but the major activator of SAPK/JNK is a MAPK kinase called SAPK/ERK kinase-1 (SEK1) or mitogen-activated protein kinase kinase 4 (MKK4) (hereinafter, SEK1 and MKK4 are frequently referred to as “SEK1/MKK4”) {Lin, A. et al.,
Science,
268: 286-290 (1995); Sanchez, I.,
Nature,
372: 794-798 (1994); and Moriguchi, T. et al.,
J. Biol. Chem.,
270: 12969-12972 (1995)}. Therefore, with respect to the classical MAP kinase, the classical MAPK kinase functions as an activation factor in the upstream of the signal transduction pathway, and a novel MAP kinase is phosphorylated (activated) specifically by a different MAPK kinase. With respect to a MAPKK kinase in the upstream of a pathway leading to SAPK/JNK, a kinase called MEKK is known, but the existence of other kinases capable of functioning as a MAPKK kinase is not known.
In addition to SAPK/JNK mentioned above, a kinase similar to MAP kinase, which is simply called “p38” after its molecular weight, is also known in the art. This kinase has been identified and cloned as a protein which is tyrosine phosphorylated in an early stage after stimulating lymphocytes {Han, J. et al.,
Science,
265: 808-811 (1994)}. Contemporaneously with p38, a protein which binds to a cytokine-suppressive anti-inflammatory drug (CSAID; a drug for suppressing the production of anti-inflammatory cytokines in lymphocytes) has been independently identified and called CSAID binding protein (CSBP) {Lee, J. C. et al.,
Nature,
372: 739-746 (1994)}. At present, this protein is confirmed to be identical with p38. Further, MPK2, an independently isolated kinase which is activated by stress stimuli, is also found to be identical with p38 {Rouse, J. et al.,
Cell,
78: 1027-1037 (1994)} (Hereinafter, p38, CSBP and MPK2 are frequently referred to as “p38”). With respect to the above-mentioned TXY sequence (X is a predetermined amino acid residue) necessary for activating a MAP kinase, the amino acid residue “X” is “G” in p38, and p38 is activated as a result of the phosphorylation of the Thr and Tyr residues by a sole MAPK kinase in the upstream thereof. MKK3 and MKK6 are known as MAPK kinases wh
Matsuzaki Osamu
Moriguchi Tetsuo
Nishida Eisuke
Asahi Kasei Kabushikiki Kaisha
Mertz Prema
Young & Thompson
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