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Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding
Published on: June 9, 2017
Essential role of Gab1 for signaling by the c-Met receptor in vivo
M Sachs1, H Brohmann, D Zechner
1Department of Growth and Differentiation, Max-Delbrueck-Center for Molecular Medicine, 13092 Berlin, Germany.
Abstract:
The docking protein Gab1 binds phosphorylated c-Met receptor tyrosine kinase directly and mediates signals of c-Met in cell culture. Gab1 is phosphorylated by c-Met and by other receptor and nonreceptor tyrosine kinases. Here, we report the functional analysis of Gab1 by targeted mutagenesis in the mouse, and compare the phenotypes of the Gab1 and c-Met mutations. Gab1 is essential for several steps in development: migration of myogenic precursor cells into the limb anlage is impaired in Gab1-/- embryos. As a consequence, extensor muscle groups of the forelimbs are virtually absent, and the flexor muscles reach less far. Fewer hindlimb muscles exist, which are smaller and disorganized. Muscles in the diaphragm, which also originate from migratory precursors, are missing. Moreover, Gab1-/- embryos die in a broad time window between E13.5 and E18.5, and display reduced liver size and placental defects. The labyrinth layer, but not the spongiotrophoblast layer, of the placenta is severely reduced, resulting in impaired communication between maternal and fetal circulation. Thus, extensive similarities between the phenotypes of c-Met and HGF/SF mutant mice exist, and the muscle migration phenotype is even more pronounced in Gab1-/-:c-Met+/- embryos. This is genetic evidence that Gab1 is essential for c-Met signaling in vivo. Analogy exists to signal transmission by insulin receptors, which require IRS1 and IRS2 as specific docking proteins.
Insights
Gab1 is crucial for embryonic development, mediating signals from the c-Met receptor tyrosine kinase. Gab1 deficiency impairs muscle formation and placental function, highlighting its essential role in vivo.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Gab1 is a docking protein that binds and mediates signals from the phosphorylated c-Met receptor tyrosine kinase.
- Gab1 is phosphorylated by c-Met and other tyrosine kinases, playing a role in cellular signaling pathways.
Purpose of the Study:
- To functionally analyze Gab1 through targeted mutagenesis in mice.
- To compare the developmental phenotypes of Gab1 and c-Met mutations in vivo.
Main Methods:
- Targeted mutagenesis in mice to create Gab1 knockout embryos (Gab1-/-).
- Phenotypic analysis of Gab1-/- embryos, including developmental defects, muscle formation, and placental structure.
- Comparison of Gab1-/- phenotypes with known c-Met and HGF/SF mutant phenotypes.
Main Results:
- Gab1-/- embryos exhibit impaired migration of myogenic precursor cells, leading to severe muscle defects in limbs and diaphragm.
- Gab1-/- embryos show reduced liver size, placental defects (reduced labyrinth layer), and embryonic lethality between E13.5 and E18.5.
- Phenotypes of Gab1-/- mice closely resemble those of c-Met and HGF/SF mutants, with muscle migration defects being more pronounced in compound Gab1-/-:c-Met+/- embryos.
Conclusions:
- Gab1 is essential for multiple developmental processes in vivo, including muscle precursor cell migration and placental development.
- Gab1 plays a critical role in mediating c-Met signaling pathways essential for embryonic development.
- Gab1 acts as a key docking protein in the c-Met signaling cascade, analogous to IRS proteins in insulin receptor signaling.
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