Dok-7
Encyclopedia
Dok-7 is a non-catalytic cytoplasmic adaptor protein that is expressed specifically in muscle and is essential for the formation of neuromuscular synapses. Further, Dok-7 contains pleckstrin homology (PH) and phosphotyrosine-binding (PTB) domains that are critical for Dok-7 function. Finally, mutations in Dok-7 are commonly found in patients with limb-girdle congenital myasthenia.
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.
Dok-7 regulates neuromuscular synapse formation by activating MuSK
The formation of neuromuscular synapses requires the muscle-specific receptor tyrosine kinase (MuSK). In mice genetically mutant for MuSK, acetylcholine receptors (AChRs) fail to cluster and motor neurons fail to differentiate. Because Dok-7 mutant mice are indistinguishable from MuSK mutant mice, these observations suggest Dok-7 might regulate MuSK activation. Indeed, Dok-7 binds phosphorylated MuSK and activates MuSK in purified protein preparations and in muscle in-vivo by transgenic overexpression. Furthermore, the nerve-derived organizing factor Agrin fails to stimulate MuSK activation in muscle cells genetically null for Dok-7. Thus, Dok-7 is both necessary and sufficient for the activation of MuSK.Dok-7 signaling
The requirement for MuSKMusk
Musk is a class of aromatic substances commonly used as base notes in perfumery. They include glandular secretions from animals such as the musk deer, numerous plants emitting similar fragrances, and artificial substances with similar odors. Musk was a name originally given to a substance with a...
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
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
does not form.
Upon activation by its ligand agrin
Agrin
Agrin is a large proteoglycan whose best characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. In humans, this protein is encoded by the AGRN...
, MuSK signals via the proteins called Dok-7 and rapsyn, to induce "clustering" of acetylcholine receptors (AChR
ACHR
ACHR may refer to:*American Convention on Human Rights*Asian Centre for Human Rights*Acetylcholine receptor...
). 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
ACHR
ACHR may refer to:*American Convention on Human Rights*Asian Centre for Human Rights*Acetylcholine receptor...
, 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.