2. Academic Validation
  3. Phosphoproteome Profiling of the Receptor Tyrosine Kinase MuSK Identifies Tyrosine Phosphorylation of Rab GTPases

Phosphoproteome Profiling of the Receptor Tyrosine Kinase MuSK Identifies Tyrosine Phosphorylation of Rab GTPases

  • Mol Cell Proteomics. 2022 Apr;21(4):100221. doi: 10.1016/j.mcpro.2022.100221.
Hanna G Budayeva 1,  Arundhati Sengupta-Ghosh 2,  Lilian Phu 3,  John G Moffat 4,  Gai Ayalon 2,  Donald S Kirkpatrick 5
Affiliations

Affiliations

  • 1 Microchemistry, Proteomics, and Lipidomics Department, Genentech, Inc, South San Francisco, California, USA. Electronic address: budayeva.hanna@gene.com.
  • 2 Neuroscience Department, Genentech, Inc, South San Francisco, California, USA.
  • 3 Microchemistry, Proteomics, and Lipidomics Department, Genentech, Inc, South San Francisco, California, USA.
  • 4 Biochemical and Cellular Pharmacology and Computational Drug Design, Genentech, Inc, South San Francisco, California, USA.
  • 5 Microchemistry, Proteomics, and Lipidomics Department, Genentech, Inc, South San Francisco, California, USA. Electronic address: dkirkpatrick@interlinetx.com.
PMID: 35227894 DOI: 10.1016/j.mcpro.2022.100221
Abstract

Muscle-specific receptor tyrosine kinase (MuSK) agonist Antibodies were developed 2 decades ago to explore the benefits of receptor activation at the neuromuscular junction. Unlike agrin, the endogenous agonist of MuSK, agonist Antibodies function independently of its coreceptor low-density lipoprotein receptor-related protein 4 to delay the onset of muscle denervation in mouse models of ALS. Here, we performed dose-response and time-course experiments on myotubes to systematically compare site-specific phosphorylation downstream of each agonist. Remarkably, both agonists elicited similar intracellular responses at known and newly identified MuSK signaling components. Among these was inducible tyrosine phosphorylation of multiple Rab GTPases that was blocked by MuSK inhibition. Importantly, mutation of this site in Rab10 disrupts association with its effector proteins, molecule interacting with CasL 1/3. Together, these data provide in-depth characterization of MuSK signaling, describe two novel MuSK inhibitors, and expose phosphorylation of Rab GTPases downstream of receptor tyrosine kinase activation in myotubes.

Keywords

Rab GTPases; c2c12; muscle-specific receptor tyrosine kinase; phosphoproteomics.

Figures
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  • HY-15590
    98.92%, Trk Receptor抑制剂
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