Dok-7

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Dok-7 is a cytoplasmic protein containing a Plekstrin Homology domain and a PTB domain which serves an essential signaling step in the formation of the Neuromuscular Junction (NMJ).

[edit] Dok-7 is required for formation of the Neuromuscular Junction

During development, the growing end of motor neuron axons secrete a protein called agrin. This protein binds to several receptors on the surface of skeletal muscle. The receptor which seems to be required for formation of the neuromuscular junction (NMJ) is called MuSK (Muscle specific kinase). MuSK is a receptor tyrosine kinase - meaning that it induces cellular signaling by causing the addition of phosphate molecules to particular tyrosines on itself, and on proteins which bind the cytoplasmic domain of the receptor.

[edit] Dok-7 signaling

The requirement for MuSK in the formation of the NMJ was primarily demonstrated by mouse "knockout" studies. In mice which are deficient for either agrin or MuSK, the neuromuscular junction does not form.

Upon activation by its ligand agrin, MuSK signals via the proteins called Dok-7 and rapsyn, to induce "clustering" of acetylcholine receptors (AChR). Cell signaling downstream of MuSK requires Dok-7. Mice which lack this protein fail to develop endplates. Further, forced expression of Dok-7 induces the tyrosine phosphorylation, and thus the activation of MuSK. Dok-7 interacts with MuSK by way of protein "domain" called a "PTB domain."

In addition to the AChR, MuSK, and Dok-7 other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the neuromuscular junction - a structure which is required to transmit nerve impulses to the muscle, and thus initiating muscle contraction.

[edit] References

[1] Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury

[2] The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo

[3] Agrin acts via a MuSK receptor complex

[4] Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies

[5] The synaptic muscle-specific kinase (MuSK) complex: new partners, new functions.

[6] The muscle protein Dok-7 is essential for neuromuscular synaptogenesis.