Tyrosine Kinases Compete for Growth Hormone Receptor Binding and Regulate Receptor Mobility and Degradation

Chhabra, Yash; Seiffert, Pernille; Gormal, Rachel S.; Vullings, Manon; Lee, Christine Mei Mei; Wallis, Tristan P.; Dehkhoda, Farhad; Indrakumar, Sowmya; Jacobsen, Nina L.; Lindorff‐Larsen, Kresten; Durisic, Nela; Waters, Michael J.; Meunier, Frédéric A.; Kragelund, Birthe B.; Brooks, Andrew J.

doi:10.2139/ssrn.4260495

Cited by 5 publications

(9 citation statements)

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“…Structural changes in the GHR-ECD induced by the ligand result in an altered ratio of JAK2-STAT5 to ERK1/2 signalling, which has also been shown for other receptors, including the Prolactin Receptor (PRLR) and Erythropoietin receptors (EpoR) (32)(33)(34)(35). The impact of the competitive binding of PKs for the GHR receptor nanoscale organisation and two alternative signaling pathways was recently demonstrated (27). Upon growth hormone (GH) addition and Lyn binding/activation (ERK1/2 pathway), the GHR redistributes into larger clusters on the plasma membrane.…”

Section: Protein Kinase Cluster By Association With Plasma Membrane R...mentioning

confidence: 73%

“…4A). This clustering has been shown to be highly dependent upon competitive binding of two PKs with distinct downstream signalling (27). It is unclear whether these clusters are fostering the formation of dimers (31), which is needed for effective signalling (Fig.…”

Section: Protein Kinase Cluster By Association With Plasma Membrane R...mentioning

confidence: 99%

“…Since receptors and associated PKs can potentially participate in more than one signaling cascade, the mechanism by which they can favour one over the other is still mostly elusive. Other factors in determining the nature and strength of the output signal are (i) the probability of ligand/binding, activation and dissociation (104), (ii) their multimeric state (27,31), (iii) their diffusive and clustering properties (105), the local concentration (106) (Fig. 5).…”

Section: Pk Nanoclustering For Optimal Output Signalmentioning

confidence: 99%

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Location, Location, Location: Protein kinase nanoclustering for optimized signalling output

Gormal,

Martínez-Mármol,

Brooks

et al. 2023

Preprint

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Protein kinases (PKs) are proteins at the core of cellular signalling and are thereby responsible for most of the cellular physiological processes and their regulations. As for all cellular proteins, they are subjected to Brownian thermal energy that tends to homogenise their distribution throughout the volume of the cell. To access their substrates and perform their critical functions, PKs localisation is therefore tightly regulated in space and time, relying upon a range of clustering mechanisms. These include post-translational modifications, protein-protein and protein-lipid interactions as well as liquid-liquid phase separation, allowing spatial restriction and ultimately regulating access to their substrates. In this review, we will mainly focus on key mechanisms mediating PK nanoclustering in physiological and pathophysiological processes. We propose that PK nanoclusters act as a cellular unit of signalling output capable of integration and regulation in space and time. We will specifically outline the various super-resolution microscopy approaches currently used to elucidate the mechanisms driving PK nanoscale clustering and explore the pathological consequences of altered kinase clustering in the context of neurodegenerative disorders, inflammation, and cancer.

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Section: Protein Kinase Cluster By Association With Plasma Membrane R...mentioning

confidence: 73%

Section: Protein Kinase Cluster By Association With Plasma Membrane R...mentioning

confidence: 99%

Section: Pk Nanoclustering For Optimal Output Signalmentioning

confidence: 99%

See 1 more Smart Citation

Location, Location, Location: Protein kinase nanoclustering for optimized signalling output

Gormal,

Martínez-Mármol,

Brooks

et al. 2023

Preprint

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“…It has been suggested that JAK2 and PRLR interact constitutively in cells (Campbell et al, 1994; Rui et al, 1994) although recent data for the GHR have shown that the Src family kinase Lyn competes for this site (Chhabra et al, n.d.). Thus, given our observations that residues from LID1 form lipid-specific contacts with the membrane constituents using the same region covering the binding interface with the FERM domain of JAK2, we decided to explore the structure and dynamics of the JAK2(FERM-SH2):PRLR(LID1) complex near lipid bilayers ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

The prolactin receptor scaffolds Janus kinase 2 via co-structure formation with phosphoinositide-4,5-bisphosphate

Araya-Secchi

Bugge

Seiffert

et al. 2022

Preprint

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Class 1 cytokine receptors transmit signals through the membrane by a single transmembrane helix to an intrinsically disordered cytoplasmic domain that lacks kinase activity. While specific binding to phosphoinositides has been reported for the prolactin receptor (PRLR), the role of lipids in PRLR signalling is unclear. Using an integrative approach combining NMR spectroscopy, cellular signalling experiments, computational modelling and simulation, we demonstrate co-structure formation of the disordered intracellular domain of the human PRLR, the membrane constituent phosphoinositide-4,5- bisphosphate (PI(4,5)P2) and the FERM-SH2 domain of the Janus kinase 2 (JAK2). We find that the complex leads to accumulation of PI(4,5)P2 at the transmembrane helix interface and that mutation of residues identified to interact specifically with PI(4,5)P2 negatively affects PRLR-mediated activation of signal transducer and activator of transcription 5 (STAT5). Facilitated by co-structure formation, the membrane-proximal disordered region arranges into an extended structure. We suggest that the co-structure formed between PRLR, JAK2 and PI(4,5)P2 locks the juxtamembrane disordered domain of the PRLR in an extended structure, enabling signal relay from the extracellular to the intracellular domain upon ligand binding. The co-structure exists in different states which could be relevant for turning signalling on and off. Similar co-structures may be relevant for other non-tyrosine kinase receptors.

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“…The protein concentration was determined from the absorbance at 492 nm using ε = 82,000 M −1 cm −1 . Thermophoresis was measured with a 3p‐Dss1 concentration of 40 nM and increasing concentrations of added Dma1‐FHA following the protocol from Chhabra et al (2023).…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation of Schizosaccharomyces pombe Dss1 mediates direct binding to the ubiquitin‐ligase Dma1 in vitro

Jacobsen

Bloch²,

Millard

et al. 2023

Protein Science

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Intrinsically disordered proteins (IDPs) are often multifunctional and frequently posttranslationally modified. Deleted in split hand/split foot 1 (Dss1 – Sem1 in budding yeast) is a highly multifunctional IDP associated with a range of protein complexes. However, it remains unknown if the different functions relate to different modified states. In this work we show that S. pombe Dss1 is a substrate for casein kinase 2 in vitro and we identify three phosphorylated threonines in its linker region separating two known disordered ubiquitin binding motifs. Phosphorylations of the threonines had no effect on ubiquitin binding, but caused a slight destabilization of the C‐terminal α‐helix and mediated a direct interaction with the forkhead‐associated domain (FHA) of the RING‐FHA E3‐ubiquitin ligase defective in mitosis 1 (Dma1). The phosphorylation sites are not conserved and are absent in human Dss1. Sequence analyses revealed that the Txx(E/D) motif, which is important for phosphorylation and Dma1 binding, is not linked to certain branches of the evolutionary tree. Instead, we find that the motif appears randomly, supporting the mechanism of ex nihilo evolution of novel motifs. In support of this, other threonine‐based motifs, although frequent, are non‐conserved in the linker, pointing to additional functions connected to this region. We suggest that Dss1 acts as an adaptor protein that docks to Dma1 via the phosphorylated FHA‐binding motifs, while the C‐terminal α‐helix is free to bind mitotic septins, thereby stabilizing the complex. The presence of Txx(D/E) motifs in the disordered regions of certain septin subunits may be of further relevance to the formation and stabilization of these complexes.This article is protected by copyright. All rights reserved.

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Tyrosine Kinases Compete for Growth Hormone Receptor Binding and Regulate Receptor Mobility and Degradation

Cited by 5 publications

References 0 publications

Location, Location, Location: Protein kinase nanoclustering for optimized signalling output

Location, Location, Location: Protein kinase nanoclustering for optimized signalling output

The prolactin receptor scaffolds Janus kinase 2 via co-structure formation with phosphoinositide-4,5-bisphosphate

Phosphorylation of Schizosaccharomyces pombe Dss1 mediates direct binding to the ubiquitin‐ligase Dma1 in vitro

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