Netrin Synergizes Signaling and Adhesion through DCC

Meijers, Rob; Smock, Robert G.; Zhang, Yan; Wang, Jia-Huai

doi:10.1016/j.tibs.2019.10.005

Cited by 37 publications

(28 citation statements)

References 47 publications

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“…4a) and thereby enhancing the weak D1mediated self-association. We note with interest that recent structural studies of deleted in colorectal cancer (DCC), a netrin receptor, important for axon navigation, suggests the associations of DCC with both its extracellular and intracellular binding partners play roles in mediating the receptor clustering [52][53][54][55] .…”

Section: Discussionmentioning

confidence: 99%

Structural basis of liprin-α-promoted LAR-RPTP clustering for modulation of phosphatase activity

et al. 2020

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Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are cell adhesion molecules involved in mediating neuronal development. The binding of LAR-RPTPs to extracellular ligands induces local clustering of LAR-RPTPs to regulate axon growth and synaptogenesis. LAR-RPTPs interact with synaptic liprin-α proteins via the two cytoplasmic phosphatase domains, D1 and D2. Here we solve the crystal structure of LAR_D1D2 in complex with the SAM repeats of liprin-α3, uncovering a conserved two-site binding mode. Cellular analysis shows that liprin-αs robustly promote clustering of LAR in cells by both the liprin-α/LAR interaction and the oligomerization of liprin-α. Structural analysis reveals a unique homophilic interaction of LAR via the catalytically active D1 domains. Disruption of the D1/D1 interaction diminishes the liprin-α-promoted LAR clustering and increases tyrosine dephosphorylation, demonstrating that the phosphatase activity of LAR is negatively regulated by forming clusters. Additionally, we find that the binding of LAR to liprin-α allosterically regulates the liprin-α/liprin-β interaction.

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Section: Discussionmentioning

confidence: 99%

Structural basis of liprin-α-promoted LAR-RPTP clustering for modulation of phosphatase activity

et al. 2020

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“…We found that tumor mutations of members of the Netrin family showed a unique distribution pattern for cancer type, protein structure, and ethnic group. It is worth noting that a significant number of missense or truncating mutations have been found in the Laminin N-terminal and EGF domains that interact with related receptors 55,56 and the regulatory localization of the NTR domain 57,58 . Thus, the molecular mechanisms related to receptor affinity and spatial localization should be thoroughly investigated at the level of structural biology and biochemistry.…”

Section: Discussionmentioning

confidence: 99%

The pan-cancer landscape of netrin family reveals potential oncogenic biomarkers

Hao

Lin

et al. 2020

Sci Rep

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Recent cancer studies have found that the netrin family of proteins plays vital roles in the development of some cancers. However, the functions of the many variants of these proteins in cancer remain incompletely understood. In this work, we used the most comprehensive database available, including more than 10000 samples across more than 30 tumor types, to analyze the six members of the netrin family. We performed comprehensive analysis of genetic change and expression of the netrin genes and analyzed epigenetic and pathway relationships, as well as the correlation of expression of these proteins with drug sensitivity. Although the mutation rate of the netrin family is low in pan-cancer, among the tumor patients with netrin mutations, the highest number are Uterine Corpus Endometrial Carcinoma patients, accounting for 13.6% of cases (54 of 397). Interestingly, the highest mutation rate of a netrin family member is 38% for NTNG1 (152 of 397). Netrin proteins may participate in the development of endocrine-related tumors and sex hormone-targeting organ tumors. Additionally, the participation of NTNG1 and NTNG2 in various cancers shows their potential for use as new tumor markers and therapeutic targets. this analysis provides a broad molecular perspective of this protein family and suggests some new directions for the treatment of cancer. Cytokines, growth factors, angiogenic factors, and extracellular proteases are secreted to the outside of the cell to produce biological functions 1. These secreted proteins participate in the immune regulation of chronic inflammation 2,3 and the occurrence of lipid metabolism diseases 4 , but also play important roles in tumor invasion, metastasis, immunity, and drug resistance 5-8. For example, CD317 and EGFR are secreted proteins that are potential diagnostic markers for non-small cell lung cancer 9. CD63 is secreted by melanoma into the blood and can be used as a protein marker 10. HGF inhibits the treatment of RAF inhibitors of BRAF mutant melanoma 11. The netrins are neuroguiding factors with axonal guiding function, and are similar to laminin in structure. Netrins were first discovered in C. elegans in 1990 12 , and this family of proteins includes the secreted proteins Netrin-1 (NTN1), Netrin-3 (NTN3), Netrin-4 (NTN4), and Netrin-5 (NTN5). The secreted proteins have a common domain structure, with an N-terminal laminin repeat (Laminin N-terminal), three cysteine-rich EGF modules (V-1, V-2, and V-3), and a positively charged C-terminal domain (NTR) 13. The netrin family also includes two membrane-binding proteins, Netrin-G1 (NTNG1) and Netrin-G2 (NTNG2) 14. Although these proteins also have Laminin N-terminal and Laminin EGF domains, their ends have different functions due to GPI 15. The major binding receptors of the secreted netrin proteins are DCC and UNC5 homologue family UNC5A-D, which are both dependent receptors. Netrin binding to a receptor promotes cell survival, proliferation, and differentiation, and without netrin binding, the receptor induces apoptosis 16,17....

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“…We showed that draxin controls axon guidance through netrin-1 receptors, Deleted in colorectal cancer (Dcc) and Neogenin (Neo1) ( Ahmed et al, 2011 ; Shinmyo et al, 2015 ). Draxin has also been shown to modulate netrin-1-mediated axon guidance and fasciculation ( Gao et al, 2015 ; Liu et al, 2018 ; Meijers et al, 2020 ). In this review, we highlight possible roles of draxin/netrin-1 signaling in the development of spinal commissural axons, corpus callosum, and thalamocortical axons.…”

Section: Introductionmentioning

confidence: 99%

Multiple Functions of Draxin/Netrin-1 Signaling in the Development of Neural Circuits in the Spinal Cord and the Brain

Ahmed

Shinmyo

2021

Front. Neuroanat.

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Axon guidance proteins play key roles in the formation of neural circuits during development. We previously identified an axon guidance cue, named draxin, that has no homology with other axon guidance proteins. Draxin is essential for the development of various neural circuits including the spinal cord commissure, corpus callosum, and thalamocortical projections. Draxin has been shown to not only control axon guidance through netrin-1 receptors, deleted in colorectal cancer (Dcc), and neogenin (Neo1) but also modulate netrin-1-mediated axon guidance and fasciculation. In this review, we summarize the multifaceted functions of draxin and netrin-1 signaling in neural circuit formation in the central nervous system. Furthermore, because recent studies suggest that the distributions and functions of axon guidance cues are highly regulated by glycoproteins such as Dystroglycan and Heparan sulfate proteoglycans, we discuss a possible function of glycoproteins in draxin/netrin-1-mediated axon guidance.

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Netrin Synergizes Signaling and Adhesion through DCC

Cited by 37 publications

References 47 publications

Structural basis of liprin-α-promoted LAR-RPTP clustering for modulation of phosphatase activity

Structural basis of liprin-α-promoted LAR-RPTP clustering for modulation of phosphatase activity

The pan-cancer landscape of netrin family reveals potential oncogenic biomarkers

Multiple Functions of Draxin/Netrin-1 Signaling in the Development of Neural Circuits in the Spinal Cord and the Brain

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