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

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 lipoprot...

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Autores principales: Budayeva, Hanna G., Sengupta-Ghosh, Arundhati, Phu, Lilian, Moffat, John G., Ayalon, Gai, Kirkpatrick, Donald S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8972003/
https://www.ncbi.nlm.nih.gov/pubmed/35227894
http://dx.doi.org/10.1016/j.mcpro.2022.100221
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author Budayeva, Hanna G.
Sengupta-Ghosh, Arundhati
Phu, Lilian
Moffat, John G.
Ayalon, Gai
Kirkpatrick, Donald S.
author_facet Budayeva, Hanna G.
Sengupta-Ghosh, Arundhati
Phu, Lilian
Moffat, John G.
Ayalon, Gai
Kirkpatrick, Donald S.
author_sort Budayeva, Hanna G.
collection PubMed
description 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.
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spelling pubmed-89720032022-04-04 Phosphoproteome Profiling of the Receptor Tyrosine Kinase MuSK Identifies Tyrosine Phosphorylation of Rab GTPases Budayeva, Hanna G. Sengupta-Ghosh, Arundhati Phu, Lilian Moffat, John G. Ayalon, Gai Kirkpatrick, Donald S. Mol Cell Proteomics Research 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. American Society for Biochemistry and Molecular Biology 2022-02-26 /pmc/articles/PMC8972003/ /pubmed/35227894 http://dx.doi.org/10.1016/j.mcpro.2022.100221 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research
Budayeva, Hanna G.
Sengupta-Ghosh, Arundhati
Phu, Lilian
Moffat, John G.
Ayalon, Gai
Kirkpatrick, Donald S.
Phosphoproteome Profiling of the Receptor Tyrosine Kinase MuSK Identifies Tyrosine Phosphorylation of Rab GTPases
title Phosphoproteome Profiling of the Receptor Tyrosine Kinase MuSK Identifies Tyrosine Phosphorylation of Rab GTPases
title_full Phosphoproteome Profiling of the Receptor Tyrosine Kinase MuSK Identifies Tyrosine Phosphorylation of Rab GTPases
title_fullStr Phosphoproteome Profiling of the Receptor Tyrosine Kinase MuSK Identifies Tyrosine Phosphorylation of Rab GTPases
title_full_unstemmed Phosphoproteome Profiling of the Receptor Tyrosine Kinase MuSK Identifies Tyrosine Phosphorylation of Rab GTPases
title_short Phosphoproteome Profiling of the Receptor Tyrosine Kinase MuSK Identifies Tyrosine Phosphorylation of Rab GTPases
title_sort phosphoproteome profiling of the receptor tyrosine kinase musk identifies tyrosine phosphorylation of rab gtpases
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8972003/
https://www.ncbi.nlm.nih.gov/pubmed/35227894
http://dx.doi.org/10.1016/j.mcpro.2022.100221
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