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Identification of CrkL-SH3 binding proteins from embryonic murine brain: implications for Reelin signaling during
Mujeeburahim Cheerathodi1, Bryan A Ballif
1Department of Biology, University of Vermont , 120A Marsh Life Science Building, 109 Carrigan Drive, Burlington, Vermont 05405, United States.
Abstract:
The Crk and Crk-like (CrkL) adaptor proteins play important roles in numerous signaling pathways, bridging tyrosine kinase substrates to downstream signaling effectors by virtue of their phosphotyrosine-binding SH2 domains and their effector-binding SH3 domains. Critical to understanding the diverse roles of Crk/CrkL is the identification of tissue- and signal-specific tyrosine phosphorylated substrates to which they are recruited and the tissue-specific effector proteins they chaperone into signaling complexes. Crk and CrkL are known biochemically and genetically to be essential mediators of Reelin/Disabled-1 (Dab1) signaling, which governs proper mammalian brain development. Multimeric Reelin clusters its receptors as well as the receptor-bound intracellular scaffolding protein Dab1. Clustering induces Fyn/Src-dependent Dab1 tyrosine phosphorylation, which recruits Crk/CrkL and SH3-bound effectors. Previously, 21 Crk/CrkL-SH3 binding proteins were identified from diverse cell types. We present here the proteomic identification of 101 CrkL-SH3 binding proteins from embryonic murine brain. The identified proteins are enriched in the Crk/CrkL-SH3 binding motif and signaling activities regulating cell adhesion and motility. These results suggest Reelin-induced Dab1 tyrosine phosphorylation may generate a multifaceted signaling scaffold containing a rich array of Crk/CrkL-SH3 binding effectors and may explain a growing diversity of cellular activities suggested to be influenced by Reelin/Dab1 signaling.
Insights
Crk and Crk-like (CrkL) proteins link signaling pathways. Researchers identified 101 CrkL-SH3 binding proteins in embryonic mouse brain, revealing new roles in cell adhesion and motility.
Area of Science:
- Molecular Biology
- Neuroscience
- Cell Signaling
Background:
- Crk and Crk-like (CrkL) adaptor proteins are crucial for signal transduction, utilizing SH2 and SH3 domains to connect tyrosine kinases with downstream effectors.
- These proteins are essential for Reelin/Disabled-1 (Dab1) signaling, a key pathway in mammalian brain development.
Purpose of the Study:
- To identify novel CrkL-SH3 binding proteins in the embryonic murine brain.
- To understand the role of these interactions in Reelin/Dab1 signaling and its impact on cellular functions.
Main Methods:
- Proteomic analysis was employed to identify CrkL-SH3 binding proteins from embryonic murine brain tissue.
- Bioinformatic analysis was used to assess the enrichment of specific motifs and signaling activities within the identified protein set.
Main Results:
- 101 CrkL-SH3 binding proteins were identified in the embryonic murine brain, significantly expanding the previously known interactome.
- The identified proteins showed enrichment for the Crk/CrkL-SH3 binding motif.
- Enriched signaling activities included those regulating cell adhesion and motility.
Conclusions:
- Reelin-induced Dab1 tyrosine phosphorylation creates a complex signaling scaffold with numerous Crk/CrkL-SH3 binding effectors.
- These findings suggest a broader role for Reelin/Dab1 signaling in regulating diverse cellular activities, including cell adhesion and motility.
