Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1998-04-28
2000-02-29
Fitzgerald, David L.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435325, 4352523, 4353201, 536 235, 530350, 514 2, C12N 1512, C07K 1471, G01N 3353
Patent
active
060307951
DESCRIPTION:
BRIEF SUMMARY
This application is a national stage application under 35 U.S.C. .sctn.371 of PCT/GB96/02179, filed Sep. 4, 1996, which claims priority to Great Britain application no. 9517992.5, filed Sep. 4, 1995.
1. Field of the Invention
This invention relates to a nucleic acid molecule encoding a type I receptor of the TGF-.beta. superfamily having modified growth inhibition, and its use.
2. Background of the Invention
Cell growth and differentiation in a multicellular organism are critically regulated by members of transforming growth factor-.beta. (TGF-.beta.) superfamily including TGF-.beta., activin/inhibin, bone morphogenetic protein (BMP), Mullerian-inhibiting substance and glial cell line-derived neurotrophic factor. TGF-.beta. is a prototype in this superfamily of structurally related molecules, and regulates cell proliferation, extracellular matrix formation, migration, adhesion and many other cellular functions important for development and homeostasis.
Certain members of the TGF-.beta. superfamily exert their biological actions through heteromeric complexes of two types (type I and type II) of transmembrane receptors with a serine/threonine kinase domain in their cytoplasmic region. Six different type I receptors have been identified in mammals (ten Dijke et al (1994) Prog. Growth Factor Res. 5:55-72), including one TGF-.beta. type I receptor (T.beta.R-I), two activin type I receptors (ActR-I and ActR-IB), two BMP type I receptors (BMPR-IA and BMPR-IB) and one additional type I receptor called ALK-1. The type I receptors have similar sizes (502-532 amino acid residues) and 60-90% amino acid sequence identities to each other in their kinase domains. In addition, type I receptors contain a conserved sequence known as the GS domain (also called type I box) in their cytoplasmic juxtamembrane region (Attisano et al (1994) Biochem. Biophys. Acta 1222:71-80). Type I receptors are more similar to each other than they are to the known type II receptors including TGF-.beta. type II receptor (T.beta.R-II) and two activin type II receptors (ActR-II and ActR-IIB), and thus form a subgroup of mammalian type I receptors in the family of receptor serine/threonine kinases.
Studies on transmembrane serine/threonine kinases have disclosed that certain members of TGF-.beta. superfamily exert their multiple effects through binding to unique sets of heteromeric complexes between type I and type II receptors. In the case of TGF-.beta., T.beta.R-II is a constitutively active kinase and capable of binding TGF-.beta. in the absence of T.beta.R-I, whereas T.beta.R-I requires T.beta.R-II for the ligand-binding. The T.beta.R-I kinase appears to be activated by formation of a hetero-oligomeric complex composed of TGF-.beta., T.beta.R-II and T.beta.R-I. In the complex, several serine and threonine residues in the GS domain of TBR-I become phosphorylated by T.beta.R-II, and the phosphorylation of GS domain is essential for TGF-.beta. signalling; however, the functional role of phosphorylated serine and threonine residues in the GS domain as well as the mechanism of signalling after the phosphorylation are largely unknown. In addition, the functional importance of the T.beta.R-I cytoplasmic region other than the GS domain has yet to be elucidated.
Mutational analyses altering serine and threonine residues in the T.beta.R-I GS domain have revealed that phosphorylation of certain serines and threonines by T.beta.R-II is essential for TGF-.beta. signalling although its signalling activity does not appear to depend on the phosphorylation of any particular serine or threonine residue in the TTSGSGSG sequence SEQ ID NO:19 of the GS domain (Wieser et al (1995) Embo. J. 14:2199-2208). In addition, recent identification of a constitutively active form of T.beta.R-I which does not require T.beta.R-II and TGF-.beta. for signalling suggested that T.beta.R-I acts as a downstream signalling molecule of T.beta.R-II (Wieser et al (1995) supra).
Despite the functional importance of the GS domain for initiating intracellular signals, little is known about
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Ichijo Hidenori
Miyazono Kohei
Saitoh Masae
Fitzgerald David L.
Ludwig Institute for Cancer Research
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