EPH receptor tyrosine kinases phosphorylate the PAR-3 scaffold protein to modulate downstream signaling networks

Banerjee, Sara L.; Lessard, Frédéric; Chartier, François; Jacquet, Kévin; Osornio-Hernandez, Ana I.; Teyssier, Valentine; Ghani, Karim; Lavoie, Noémie; Lavoie, Josée; Caruso, Manuel; Laprise, Patrick; Elowe, Sabine; Lambert, Jean‐Philippe; Bisson, Nicolas

doi:10.1016/j.celrep.2022.111031

Cited by 16 publications

(11 citation statements)

References 96 publications

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“…However, the resulting scatter plot confirmed the presence of several known EPHB2 interactors, such as FYN and YES1 Src kinases and members of the Eph receptor family (Fig. 1B) (Banerjee et al, 2022). One of the most prominent, novel hits was the E3 ubiquitin ligase and signalling hub protein MYCBP2, and its binding partner FBXO45.…”

Section: Resultsmentioning

confidence: 74%

Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor function

Chang

Banerjee

Park

et al. 2023

Preprint

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Eph receptor tyrosine kinases participate in a variety of normal and pathogenic processes during development and throughout adulthood. This versatility is likely facilitated by the ability of Eph receptors to signal through diverse cellular signalling pathways: primarily by controlling cytoskeletal dynamics, but also by regulating cellular growth, proliferation, and survival. Despite many proteins linked to these signalling pathways interacting with Eph receptors, the specific mechanisms behind such links and their coordination remain to be elucidated. In a proteomics screen for novel EPHB2 multi-effector proteins, we identified human MYC binding protein 2 (MYCBP2 or PAM or Phr1). MYCBP2 is a large signalling hub involved in diverse processes such as neuronal connectivity, synaptic growth, cell division, neuronal survival, and protein ubiquitination. Our biochemical experiments demonstrate that the formation of a complex containing EPHB2 and MYCBP2 is facilitated by FBXO45, a protein known to select substrates for MYCBP2 ubiquitin ligase activity. Formation of the MYCBP2-EPHB2 complex does not require EPHB2 tyrosine kinase activity and is destabilised by binding of ephrin-B ligands, suggesting that the MYCBP2-EPHB2 association is a prelude to EPHB2 signalling. Paradoxically, the loss of MYCBP2 results in increased ubiquitination of EPHB2 and a decrease of its protein levels suggesting that MYCBP2 stabilises EPHB2. Commensurate with this effect, our cellular experiments reveal that MYCBP2 is essential for efficient EPHB2 signalling responses in cell lines and primary neurons. Finally, our genetic studies in C. elegans provide in vivo evidence that the ephrin receptor VAB-1 functions within the MYCBP2 signalling network. Together, our results align with the similarity of neurodevelopmental phenotypes caused by MYCBP2 and EPHB2 loss of function, and our findings couple EPHB2 to a signalling effector controlling diverse cellular functions.

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Section: Resultsmentioning

confidence: 74%

Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor function

Chang

Banerjee

Park

et al. 2023

Preprint

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“…A recent study demonstrated that PARD3 Tyr residues are a substrate of EPHA4 and modulate downstream signalling. 63 The EPHA2-EPHA4 interaction has been previously observed using BioID data. 64 Based on these data, PARD3 Y378 is also a potential downstream candidate of EPHA2.…”

Section: Discussionmentioning

confidence: 75%

Integrative analysis of cancer dependency data and comprehensive phosphoproteomics data revealed the EPHA2-PARD3 axis as a cancer vulnerability in KRAS-mutant colorectal cancer

et al. 2023

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“…With the development of various PL enzymes, the PL technique has broadened the study of the kinase interactome in a spatiotemporally resolved manner. It provides an important tool and pathway for the functional study of kinases, such as p38, EGFR, and PTK7 [ 113 ]. Based on PL, the interactome of p38α has been mapped under a steady or activated state, indicating the local spatial proteome difference.…”

Section: Potential Strategies In Kinase Spatial Assaymentioning

confidence: 99%

Mapping the Protein Kinome: Current Strategy and Future Direction

Hou

Liu²

2023

Cells

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The kinome includes over 500 different protein kinases, which form an integrated kinase network that regulates cellular phosphorylation signals. The kinome plays a central role in almost every cellular process and has strong linkages with many diseases. Thus, the evaluation of the cellular kinome in the physiological environment is essential to understand biological processes, disease development, and to target therapy. Currently, a number of strategies for kinome analysis have been developed, which are based on monitoring the phosphorylation of kinases or substrates. They have enabled researchers to tackle increasingly complex biological problems and pathological processes, and have promoted the development of kinase inhibitors. Additionally, with the increasing interest in how kinases participate in biological processes at spatial scales, it has become urgent to develop tools to estimate spatial kinome activity. With multidisciplinary efforts, a growing number of novel approaches have the potential to be applied to spatial kinome analysis. In this paper, we review the widely used methods used for kinome analysis and the challenges encountered in their applications. Meanwhile, potential approaches that may be of benefit to spatial kinome study are explored.

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EPH receptor tyrosine kinases phosphorylate the PAR-3 scaffold protein to modulate downstream signaling networks

Cited by 16 publications

References 96 publications

Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor function

Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor function

Integrative analysis of cancer dependency data and comprehensive phosphoproteomics data revealed the EPHA2-PARD3 axis as a cancer vulnerability in KRAS-mutant colorectal cancer

Mapping the Protein Kinome: Current Strategy and Future Direction

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