Methods of ameliorating arthritis by modulating JNK signalsome activity
OwnerGary S. Firesteininventor
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Abstract
Methods for identifying an agent that modulates JNK signalsome mediated signal transduction are provided. As provided are methods of ameliorating an arthritis in a subject by inhibiting JNK signalsome activity in cells of the subject.
Claims53
A method of identifying an agent that modulates c-Jun N-terminal kinase (JNK) mediated signal transduction in a synoviocyte, the method comprising:
- a) contacting the synoviocyte, or an extract of a synoviocyte with a test agent;
- and
- b) detecting a change in the formation or activity of at least one protein complex selected from
- i) a JNK/MAP kinase kinase (MKK) protein complex, wherein the MKK is MKK4 or MKK7;
- ii) a JNK/MKK4/MKK7 protein complex,
- iii) a JNK interacting protein (JIP)/JNK/MKK4/MKK7 protein complex, wherein the JIP is JIP-1 or JIP-3,
- iv) a MAP kinase kinase kinase (MAP3K)/MKK4 protein complex, wherein the MAP3K is MEKK1, MEKK2, or TAK1, or
- vi) a MAP3K/MKK7 protein complex, wherein the MAP3K is MEKK1, MEKK2, or TAK1,
- in the presence of the test agent as compared to the formation or activity of the protein complex in the absence of the test agent, thereby detecting an agent that modulates JNK mediated signal transduction in a synoviocyte.
A method of identifying an agent that modulates c-Jun N-terminal kinase (JNK) mediated signal transduction in a synoviocyte, the method comprising:
- a) contacting
- 1)
- i) a c-Jun N-terminal kinase (JNK),
- ii) a MAP kinase kinase (MKK), wherein the MKK is MKK4, MKK7, or both MKK4 and MKK7, and, optionally,
- iii) a scaffold protein, under conditions suitable for JNK/MKK protein complex formation or activity, and
- 2) a test agent;
- and
- b) detecting a change in JNK/MKK protein complex formation or activity in the presence of the test agent as compared to the JNK/MKK protein complex formation or activity in the absence of the test agent, thereby detecting an agent that modulates JNK mediated signal transduction in a synoviocyte.
A method of ameliorating an arthritis associated with c-Jun N-terminal kinase (JNK) signalsome mediated signal transduction in cells of a subject, the method comprising contacting the cells of the subject with an agent that reduces or inhibits JNK/MAP kinase kinase (MKK) protein complex formation or activity, thereby reducing or inhibiting JNK signalsome mediated signal transduction in the cells and ameliorating the arthritis.
An isolated JNK signalsome protein complex, comprising a c-Jun N-terminal kinase (JNK) polypeptide, a mitogen associated protein (MAP) kinase kinase 4 (MKK4) polypeptide, and an MKK7 polypeptide.
Dependencies are inferred from the claim text.