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Jak stat signalling

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Mehedi Hossain

Cytokines signal through the JAK-STAT pathway. JAK kinases are associated with cytokine receptors and activate upon cytokine binding. Activated JAKs phosphorylate the receptor and STAT proteins in the cytoplasm. Phosphorylated STATs dimerize and translocate to the nucleus to regulate gene expression. This confers specificity to cytokine responses. Drugs that target the JAK-STAT pathway include cytokine receptor blockers and JAK inhibitors, which are used to treat conditions like transplant rejection and rheumatoid arthritis.

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JAK STAT MD. MEHEDI HOSSAIN 10/27/2017 JAK-STAT Signalling Cytokines are regulatory molecules that coordinate immune responses. Responses to cytokines include increasing or decreasing expression of membrane proteins (including cytokine receptors), cell proliferation, and secretion of effector molecules. Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action). The most typical cytokine receptor is a protein that form a stable association with a cytoplasmic tyrosine kinase known as a JAnus Kinase, or JAK, for short. This type of signalling is a direct and rapid way to turn on a set of genes. JAKs are cytosolic kinases associated with cytokine receptors. Four JAKs exist (JAK1-JAK4). Structure and function of JAK domain The FERM domain mediates the interaction with receptor complexes. The SH2 domain is a protein domain that binds to phosphorylated tyrosine residues. The JH2 pseudokinase domain regulates kinase activity of the JH1 kinase domain. P marks conserved tyrosine residues in JH1 whose phosphorylation is essential for JAK activation. N and C indicate the amino terminus and carboxy terminus. Structure and function of STAT domain The SH2 domain binds phosphorylated tyrosines. The carboxy terminus transactivation domain is required for full transcriptional activation. P marks the conserved tyrosine residue whose phosphorylation is essential for STAT activation. Mechanism of signalling The tyrosine kinase activity of JAK is activated when the regulatory molecule binds and brings two receptor molecules together to form a dimer. Dimerization brings the two JAKs into proximity, where they can phosphorylate each other. Phosphorylation further activates JAK, allowing it to phosphorylate the receptor. The phosphotyrosine residues on the receptor proteins are binding sites for STAT proteins. "STAT" stands for Signal Transducer and Activator of Transcription. The STAT proteins are considered latent transcription factors. "Latent" means that they are always present in the cytoplasm, and waiting to be activated by JAK.
JAK STAT MD. MEHEDI HOSSAIN When STAT binds to the receptor, that brings it into a position where it can be phosphorylated by JAK. Once phosphorylated, two STATs can then form a STAT dimer (each STAT molecule binds to the phosphotyrosine of the other phosphorylated STAT). The STAT dimer is an active transcription factor. It travels to the nucleus where it binds to specific sequences in the DNA. Inactivation occurs when phosphatases remove phosphate groups from various proteins in the signalling pathway. Notably, there are several different STAT proteins in cells, and activation of different cytokine receptors will result in the formation of different STAT dimers. Each STAT dimer binds to a specific DNA sequence found in the promoters of certain genes. In this way, each cytokine activates a specific set of genes to cause a specific response in the cell. The JAK-STAT system is a major signalling alternative to the second messenger system. Different patterns of JAK and STAT molecules seem to be activated by different cytokine receptors, this is supposed to play fundamental roles in conferring specificity for cytokine responses. In mammals, there are seven STAT genes, and each one binds to a different DNA sequence. This affects basic cell functions, like cell growth, differentiation and death. The JAK-STAT pathway is evolutionarily conserved, from slime molds and worms to mammals (but not fungi or plants). Drugs targeting the JAK-STAT pathway Drugs that target the JAK-STAT pathway are used to turn down the immune response. One type of drug that has been approved by the FDA is a cytokine receptor blocker derived from a monoclonal antibody. Because it is a protein, this type of drug needs to be injected. An example is Basiliximab, which is used to prevent transplant rejection. Basiliximab binds to the IL-2 receptor. Many drugs that inhibit the kinase activity of JAK are in development, and one, ruxolitinib, has been approved to treat a myeolo-proliferative disorder (a disorder in which there is abnormal proliferation of cells in the bone marrow). Tofacitinib is a JAK inhibitor that has been approved for the treatment of rheumatoid arthritis. An advantage of JAK inhibitors over receptor blocking drugs is that they are small molecule drugs that can be taken orally.

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Jak stat signalling

  • 1. JAK STAT MD. MEHEDI HOSSAIN 10/27/2017 JAK-STAT Signalling Cytokines are regulatory molecules that coordinate immune responses. Responses to cytokines include increasing or decreasing expression of membrane proteins (including cytokine receptors), cell proliferation, and secretion of effector molecules. Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action). The most typical cytokine receptor is a protein that form a stable association with a cytoplasmic tyrosine kinase known as a JAnus Kinase, or JAK, for short. This type of signalling is a direct and rapid way to turn on a set of genes. JAKs are cytosolic kinases associated with cytokine receptors. Four JAKs exist (JAK1-JAK4). Structure and function of JAK domain The FERM domain mediates the interaction with receptor complexes. The SH2 domain is a protein domain that binds to phosphorylated tyrosine residues. The JH2 pseudokinase domain regulates kinase activity of the JH1 kinase domain. P marks conserved tyrosine residues in JH1 whose phosphorylation is essential for JAK activation. N and C indicate the amino terminus and carboxy terminus. Structure and function of STAT domain The SH2 domain binds phosphorylated tyrosines. The carboxy terminus transactivation domain is required for full transcriptional activation. P marks the conserved tyrosine residue whose phosphorylation is essential for STAT activation. Mechanism of signalling The tyrosine kinase activity of JAK is activated when the regulatory molecule binds and brings two receptor molecules together to form a dimer. Dimerization brings the two JAKs into proximity, where they can phosphorylate each other. Phosphorylation further activates JAK, allowing it to phosphorylate the receptor. The phosphotyrosine residues on the receptor proteins are binding sites for STAT proteins. "STAT" stands for Signal Transducer and Activator of Transcription. The STAT proteins are considered latent transcription factors. "Latent" means that they are always present in the cytoplasm, and waiting to be activated by JAK.
  • 2. JAK STAT MD. MEHEDI HOSSAIN When STAT binds to the receptor, that brings it into a position where it can be phosphorylated by JAK. Once phosphorylated, two STATs can then form a STAT dimer (each STAT molecule binds to the phosphotyrosine of the other phosphorylated STAT). The STAT dimer is an active transcription factor. It travels to the nucleus where it binds to specific sequences in the DNA. Inactivation occurs when phosphatases remove phosphate groups from various proteins in the signalling pathway. Notably, there are several different STAT proteins in cells, and activation of different cytokine receptors will result in the formation of different STAT dimers. Each STAT dimer binds to a specific DNA sequence found in the promoters of certain genes. In this way, each cytokine activates a specific set of genes to cause a specific response in the cell. The JAK-STAT system is a major signalling alternative to the second messenger system. Different patterns of JAK and STAT molecules seem to be activated by different cytokine receptors, this is supposed to play fundamental roles in conferring specificity for cytokine responses. In mammals, there are seven STAT genes, and each one binds to a different DNA sequence. This affects basic cell functions, like cell growth, differentiation and death. The JAK-STAT pathway is evolutionarily conserved, from slime molds and worms to mammals (but not fungi or plants). Drugs targeting the JAK-STAT pathway Drugs that target the JAK-STAT pathway are used to turn down the immune response. One type of drug that has been approved by the FDA is a cytokine receptor blocker derived from a monoclonal antibody. Because it is a protein, this type of drug needs to be injected. An example is Basiliximab, which is used to prevent transplant rejection. Basiliximab binds to the IL-2 receptor. Many drugs that inhibit the kinase activity of JAK are in development, and one, ruxolitinib, has been approved to treat a myeolo-proliferative disorder (a disorder in which there is abnormal proliferation of cells in the bone marrow). Tofacitinib is a JAK inhibitor that has been approved for the treatment of rheumatoid arthritis. An advantage of JAK inhibitors over receptor blocking drugs is that they are small molecule drugs that can be taken orally.