Abstract
Muscle-specific kinase (MuSK) is a receptor tyrosine kinase absolutely required for neuromuscular junction formation. MuSK is activated by binding of motor neuron-derived Agrin to low-density lipoprotein receptor related protein 4 (Lrp4), which forms a complex with MuSK. MuSK activation and downstream signaling are critical events during the development of the neuromuscular junction. Receptor tyrosine kinases are commonly internalized upon ligand binding and crosstalk between endocytosis and signaling has been implicated. To extend our knowledge about endocytosis of synaptic proteins and its role during postsynaptic differentiation at the neuromuscular junction, we studied the stability and internalization of Lrp4, MuSK and acetylcholine receptors (AChRs) in response to Agrin. We provide evidence that MuSK but not Lrp4 internalization is increased by Agrin stimulation. MuSK kinase-activity is not sufficient to induce MuSK internalization and the absence of Lrp4 has no effect on MuSK endocytosis. Moreover, MuSK internalization and signaling are unaffected by the inhibition of Dynamin suggesting that MuSK endocytosis uses a non-conventional pathway and is not required for MuSK-dependent downstream signaling.
Highlights
The transmission of brain-derived electrical impulses to muscles depends on a specialized region referred to as the neuromuscular junction (NMJ)
In the presence of Agrin, Muscle-specific kinase (MuSK) and acetylcholine receptors (AChRs) endocytosis was increased for all time points compared to untreated samples and surface expression was decreased to around 60% after 6 h
Quantification of protein expression showed that lipoprotein receptor related protein 4 (Lrp4), MuSK and AChR stability is unaffected by Agrin stimulation (Figure 1C)
Summary
The transmission of brain-derived electrical impulses to muscles depends on a specialized region referred to as the neuromuscular junction (NMJ). The binding of Agrin to Lrp leads to the formation of an Agrin-Lrp hetero-tetramer, MuSK Endocytosis in Muscle Cells thereby inducing the dimerization of MuSK and the subsequent autophosphorylation of specific tyrosine residues within its cytoplasmic region (Watty et al, 2000; Zong et al, 2012). While the ectodomain of MuSK is mainly responsible for the interaction with the accessory receptor Lrp and the ligand-dependent receptor dimerization, the intracellular region of MuSK plays a crucial role in the transduction of signals derived from the extracellular space. Phosphorylation of specific tyrosine residues in the intracellular portion of MuSK upon Agrin stimulation creates docking sites for cytoplasmic adaptor proteins (Herbst and Burden, 2000; Okada et al, 2006). MuSK initiates downstream signaling that drives postsynaptic differentiation including the clustering of AChRs (Herbst, 2020)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
