Tyrosine kinases

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Tyrosine kinases are a group of enzymes from the protein kinase family whose task is the reversible transfer of a phosphate group ( phosphorylation ) to the hydroxyl group of the amino acid tyrosine of another protein . This significantly influences the activity of the target protein, which is why tyrosine kinases also make an important contribution to signal transmission as part of receptor systems .

Subdivision of the tyrosine kinases

  1. Membrane-bound tyrosine kinases ( EC  2.7.10.1 ). Examples: KIT , EGF receptor , insulin receptor , HER2 / new .
    1. Receptors with intrinsic tyrosine kinase activity (kinase is part of the receptor).
    2. Receptors with associated tyrosine kinase activity (kinase binds to receptor).
  2. Non-membrane bound tyrosine kinases ( EC  2.7.10.2 ). Examples: ABL1 , SRC , Janus kinases

How a tyrosine kinase receptor works with intrinsic activity

If a suitable ligand binds to the receptor, its spatial conformation ( protein structure ) changes. The formation of homodimers (two identical receptors joined together) or heterodimers (two different protein subunits join together) is induced. This activates the tyrosine kinases that are located on the cytosolic part of the receptor and specifically attach phosphate residues to certain tyrosine residues of the receptor. This means that proteins with SH2 domains can bind to these phosphorylated residues, the recruitment of which leads to the activation of intracellular signaling pathways. The proteins recruited in this way either have enzymatic activity themselves ( phospholipase C -γ, PI3 kinase) and can thus be used, for. B. phosphorylate other proteins or act as mediators whose structural change is recognized by other molecules ( Ras ). This leads to a relay cascade and amplification of the signal, as an activated protein in turn activates several proteins in the next stage of the signaling pathway, etc.

Short form:

  1. Ligand binding
  2. Dimerization (homo or hetero)
  3. Autophosphorylation
  4. Phosphorylated tyrosines are recognized by proteins with SH2 domains
  5. Signal transmission through phosphorylation cascades

Function of a receptor with associated tyrosine kinase

If a suitable ligand binds to the receptor, its spatial conformation changes. The formation of homodimers or heterodimers is induced. As a result, the Janus kinases approach each other and then phosphorylate each other (autophosphorylation). In the activated state, these proteins phosphorylate tyrosyl residues of the receptor, to which specific transcription factors (e.g. STAT ) with SH2 domains can now attach. These factors are phosphorylated and dimerized by the Janus kinases and thus show a higher DNA affinity.

Short form:

  1. Ligand binding
  2. Dimerization
  3. Approach and autophosphorylation of Janus kinase
  4. Phosphorylation of the receptor
  5. Binding of specific transcription factors via the SH2 domain
  6. Phosphorylation and dimerization of the transcription factors

Medical outlook

The addition of a phosphate residue can activate or inactivate a protein. Tyrosine kinases also form the intracellular part of the tyrosine kinase receptor system (insulin receptor, EGF receptor, NGF receptor, PDGF receptor), via which signals from growth factors enter preferentially . This makes them a sought-after target for research into new cancer drugs . Cell receptor-bound tyrosine kinases are important for embryonic development and the regeneration and maintenance of tissues. Disturbances in their function are partly responsible for diseases of the retina in diabetes mellitus , arteriosclerosis and, above all, they play a role in the development of cancer (i.e. in inducing a malignant cell change that can no longer be fully controlled in its growth). Tyrosine kinases are activated by the presence of various growth factors. A mutated cell receptor-bound tyrosine kinase can simulate the presence of growth factors and thus act as a cofactor on cell proliferation and ultimately on malignant cell transformation. Tyrosine kinase inhibitors are a class of novel drugs. For example, by inhibiting the tyrosine kinase in signal transduction, the step from extracellular to intracellular can be inhibited and thus existing therapy options for individual cancers can be expanded. This is especially true for patients with chronic myeloid leukemia (CML), advanced non-small cell lung cancer (NSCLC), or gastrointestinal stromal tumors (GIST).

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