Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Testing efficacy or toxicity of a compound or composition
Reexamination Certificate
1997-10-08
2001-04-03
Stucker, Jeffrey (Department: 1645)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Testing efficacy or toxicity of a compound or composition
C424S009100, C424S094100, C424S094500, C435S021000, C514S002600, C514S021800
Reexamination Certificate
active
06210654
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the Jak family of kinases and their role in the cellular response to the binding of cytokines to their respective receptors. The invention relates more specifically to the cytoki-induced activation of at least one member of a Jak kinase family, to the identification of interactions between specific cytokines and members of the Jak kinase family, and to compounds, compositions and methods relating to the regulation of this interaction.
2. Description of the Background Art
The growth, differentiation and function of eukaryotic cells is regulated in large part by extracellular factors, referred to generally as cytokines herein. These cytokines induce cellular responses by binding to their respective receptors. The receptors for cytokines fall into two major families, the cytokine receptor superfamily and the tyrosine kinase receptor superfamily.
Receptors belonging to the tyrosine kinase receptor superfamily are characterized by the presence of an identifiable cytoplasmic tyrosine kinase domain involved in the transduction of the cytokine-receptor binding signal. Members of this receptor family have been further classified into three structural subgroups (Yarden et al.,
Ann. Rev. Biochem.
57: 443-478 (1988). Members of the first subgroup are characterized as monomeric with two cysteine rich sequence repeat regions within their extracellular domains and include, e.g., the receptor for epidermal growth factor (EGF) and TGF-&agr; (see, e.g., Ullrich et al.,
Nature
309: 418-425 (1984)). Members of the second subgroup are characterized as functioning as heterotetramers and include the receptors for insulin (Ullrich, supra, (1985); Ebina et al.,
Cell
40: 747-758 (1985)) and insulin-like growth factor-1 (IGF-1) (Ullrich et al.,
EMBO J.
5:2503-2512 (1986)). Members of the third subgroup are characterized by the presence of conserved repeat structures and the interruption of their catalytic domains by long (77-107 amino acids) insertion sequences. This third subgroup includes, e.g., receptors for platelet-derived growth factor (PDGF-R) (Yarden et al.,
Nature
323: 226-232 (1986)) and the colony stimulating growth factor (CSF-1) (Sherr et al.,
Cell
41: 665-676 (1985)).
Receptors belonging to the cytokine receptor superfamily are characterized by the presence of four positionally conserved cysteines and a WSXWS (SEQ ID No. 1) motif in the extracellular domain. The family is also characterized by variably sized cytoplasmic domains that show very limited sequence similarity and which do not contain identifiable motifs that might indicate the signal transducing mechanisms. Members of the cytokine receptor superfamily include the hematopoietic growth factor receptors, receptors for growth hormone, the prolactin receptor, ciliary neurotrophic factor and others (Bazan,
Science
257:41014 413 (1992)). The receptors for interferon, although more distantly related, have been speculated to have evolved from a progenitor common to this receptor superfamily.
In spite of the lack of catalytic domains, considerable evidence suggests that signal transduction of members of the cytokine receptor superfamily involves tyrosine phosphorylation (Miyajima et al.,
Annu. Rev. Immnunol.
10:295-331 (1992); Metcalf,
Nature
339:27-30 (1989)). There is also some evidence that members of this receptor superfamily may utilize common tyrosine phosphorylation pathways for signal transduction. Specifically, binding of hematopoietic growth factors to their respective receptors have been found to induce comparable patterns of tyrosine phosphorylation (Ihle, in
Interleukins: Molecular Biology and Immunology
, Kishimoto, ed., Karger, Basel, pp. 65-106 (1992)).
While it is widely appreciated that cytokine receptors from both families described above play a key role in cellular growth regulation, little is known about the biochemical cascades triggered by the binding of cytokines to these receptors. An understanding of the steps involved in the transduction of the cytokine signal through these receptors would be useful for identifying molecules which play a critical role in signal transduction and which can serve as targets for regulating the activity of these cytokines.
A model for the study of receptor signal transduction has been developed for the erythropoietin receptor (EPOR), one of the hematopoietic growth factor receptors and a member of the cytokine receptor superfamily. Introduction of the EPOR into interleukin-3 (IL-3) dependent cell lines confers on the cells the ability to proliferate in response to EPO (D'Andrea et al.,
Cell
57:277-285 (1989); Miura et al.,
Mol. Cell Biol.
11:4895-4902 (1991)). In transfected cells, EPO induces the expression of a series of immediate early genes including c-myc, c-fos, c-pim-1 and egr-1 (Miura et al.,
Mol. Cell. Biol.
13:1788-1795 (1993)). In addition, EPO induces the rapid tyrosine phosphorylation of a series of cellular substrates (Linnekin et al.,
Proc. Natl. Acad. Sci. USA
89:6237-6241 (1992); Dusanter-Fourt et al.,
J. Biol. Chem.
267:10670-10675 (1992); Quelle and Wojchowski,
J. Biol. Chem.
266:609-614 (1991); Miura et al.,
Mol. Cell Biol.
11:4895-4902 (1991); Yoshimura and Lodish,
Mol. Cell. Biol.
12:706-715 (1992); Damen et al.,
Blood
80:1923-1932 (1992)), suggesting that EPOR may function by coupling ligand binding to the activation of a protein tyrosine kinase.
Although the importance of protein tyrosine phosphorylation for biological activities associated with EPO-EPOR binding has been clearly demonstrated, very little has been known concerning the kinases that might be involved. The rapid induction of tyrosine phosphorylation of the carboxyl region of EPOR (Miura et al.,
Mol. Cell Biol.
11:4895-4902 (1991); Yoshimura and Lodish,
Mol. Cell. Biol.
12:706-715 (1992); Dusanter-Fourt et al.,
J. Biol. Chem.
267:10670-10675 (1992)) suggests that the receptor is closely associated with a kinase, either constitutively or following ligand binding. One study Yoshimura and Lodish,
Mol. Cell. Biol.
12:706-715 (1992)) identified a non-glycosylated protein of 130 kDa that could be cross-linked with the receptor and which was tyrosine phosphorylated either in vivo or in in vitro kinase assays as assessed by its ability to be detected by an anti-phosphotyrosine antibody. Whether the 130 kDa protein was a kinase could not be determined. Recent studies (Linnekin et al.,
Proc. Natl. Acad. Sci. USA
89:6237-6241 (1992)) also identified a 97 kDa substrate of tyrosine phosphorylation which could be radiolabeled with an azido derivative of ATP, suggesting that it was a kinase. Whether the 130 kDa or 97 Kda potential kinases are previously characterized kinases was not determined.
Tyrosine phosphorylation has also been observed in response to the cytokine interferon gamma (IFN&ggr;). Recent studies (Shuai et al.,
Science
259:1808-1812 (1992)) have demonstrated that IFN&ggr; induces tyrosine phosphorylation of a 91 kDa protein, and that this 91 kDa protein migrates to the nucleus and binds a &ggr;-activated site.
Tyrosine phosphorylation has further been associated with the response to the cytokine growth hormone (GH). Studies in 3T3-F442A cells showing rapid GH-dependent tyrosyl phosphorylation of multiple proteins, tyrosyl phosphorylation of microtubule-associated protein kinases, and stimulation of microtubule-associated protein kinase activity, as well as the inhibition of these actions by inhibitors of growth hormone receptor (GHR)-associated tyrosine kinase (Campbell et al.,
J. Biol. Chem.
268:7427-7434 (1993)), suggest a central role for a GHR-associated tyrosine kinase activity in signaling by GH. In addition, the presence of a tyrosine kinase activity in a complex with GH receptor (GHR) prepared from GH-treated fibroblasts has been reported (Carter-Su. et al.,
J. Biol. Chem.
264:18654-18661 (1989); Stred et al., Endocrinol. 130: 1626-1636 (1992); Wang et al.,
J. Biol. Chem.
267: 17390-17396 (1992)). More recently, a nonreceptor tyrosyl
Ihle James
Quelle Frederick W.
Silvennoinen Ollie
Witthuhn Bruce A.
St. Jude Children's Hospital
Sterne Kessler Goldstein & Fox P.L.L.C.
Stucker Jeffrey
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