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-Syntrophin regulates ARMS localization at the neuromuscular junction and enhances EphA4 signaling in an ARMS-dependent manner

¹ Department of Biochemistry, Molecular Neuroscience Center and Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China
² Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195
³ Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016

Correspondence to Nancy Y. Ip: boip{at}ust.hk

EphA4 signaling has recently been implicated in the regulation of synapse formation and plasticity. In this study, we show that ankyrin repeat-rich membrane spanning (ARMS; also known as a kinase D–interacting substrate of 220 kD), a substrate for ephrin and neurotrophin receptors, was expressed in developing muscle and was concentrated at the neuromuscular junction (NMJ). Using yeast two-hybrid screening, we identified a PDZ (PSD-95, Dlg, ZO-1) domain protein, -syntrophin, as an ARMS-interacting protein in muscle. Overexpression of -syntrophin induced ARMS clustering in a PDZ domain–dependent manner. Coexpression of ARMS enhanced EphA4 signaling, which was further augmented by the presence of -syntrophin. Moreover, the ephrin-A1–induced tyrosine phosphorylation of EphA4 was reduced in C2C12 myotubes after the blockade of ARMS and -syntrophin expression by RNA interference. Finally, -syntrophin–null mice exhibited a disrupted localization of ARMS and EphA4 at the NMJ and a reduced expression of ARMS in muscle. Altogether, our findings suggest that ARMS may play an important role in regulating postsynaptic signal transduction through the syntrophin-mediated localization of receptor tyrosine kinases such as EphA4.

S. Luo and Y. Chen contributed equally to this paper.

Abbreviations used in this paper: AChR, acetylcholine receptor; ARMS, ankyrin repeat-rich membrane spanning; DIV, day in vitro; ERK, extracellular signal–regulated kinase; Jak, janus kinase; KD, kinase dead; mPDZ, PDZ mutant; NMJ, neuromuscular junction; nNOS, neuronal nitric oxide synthase; P, postnatal day; PDZ, PSD-95, Dlg, ZO-1; PH, pleckstrin homology; RTK, receptor tyrosine kinase; siRNA, small interference RNA; Stat, signal transducer and activator of transcription; Trk, tropomyosin-related kinase.

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