There’s more to death than life: Noncatalytic functions in kinase and pseudokinase signaling

Mace, Peter D.; Murphy, James M.

doi:10.1016/j.jbc.2021.100705

Cited by 70 publications

(72 citation statements)

References 116 publications

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“…The human kinome includes >50 pseudo-kinases that are predicted to be catalytically inactive due to the lack of important residues required for full enzymatic activity [ 1 ]. Their mechanistic role in cell signaling remains unclear, but recent structural analyses suggest a scaffolding or allosteric activity by docking additional kinases for efficient protein phosphorylation [ 1 , 2 , 3 ]. Moreover, some pseudo-kinases have retained active kinase activity through an unconventional mechanism of protein phosphorylation [ 1 , 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

SHED-Dependent Oncogenic Signaling of the PEAK3 Pseudo-Kinase

Ounoughene¹,

Fourgous²,

Boublik³

et al. 2021

Cancers

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The PEAK1 and Pragmin/PEAK2 pseudo-kinases have emerged as important components of the protein tyrosine kinase pathway implicated in cancer progression. They can signal using a scaffolding mechanism that involves a conserved split helical dimerization (SHED) module. We recently identified PEAK3 as a novel member of this family based on structural homology; however, its signaling mechanism remains unclear. In this study, we found that, although it can self-associate, PEAK3 shows higher evolutionary divergence than PEAK1/2. Moreover, the PEAK3 protein is strongly expressed in human hematopoietic cells and is upregulated in acute myeloid leukemia. Functionally, PEAK3 overexpression in U2OS sarcoma cells enhanced their growth and migratory properties, while its silencing in THP1 leukemic cells reduced these effects. Importantly, an intact SHED module was required for these PEAK3 oncogenic activities. Mechanistically, through a phosphokinase survey, we identified PEAK3 as a novel inducer of AKT signaling, independent of growth-factor stimulation. Then, proteomic analyses revealed that PEAK3 interacts with the signaling proteins GRB2 and ASAP1/2 and the protein kinase PYK2, and that these interactions require the SHED domain. Moreover, PEAK3 activated PYK2, which promoted PEAK3 tyrosine phosphorylation, its association with GRB2 and ASAP1, and AKT signaling. Thus, the PEAK1-3 pseudo-kinases may use a conserved SHED-dependent mechanism to activate specific signaling proteins to promote oncogenesis.

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Section: Introductionmentioning

confidence: 99%

SHED-Dependent Oncogenic Signaling of the PEAK3 Pseudo-Kinase

Ounoughene¹,

Fourgous²,

Boublik³

et al. 2021

Cancers

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“…Pseudokinases, proteins that adopt a protein kinase fold but are incapable of catalysing phosphorylation, are estimated to comprise ~10% of the human protein kinome [ 1 , 2 , 3 ]. Far from being dead remnants, pseudokinases specialise in a variety of other roles, including allosteric regulation of catalytically active partners, scaffolding protein–protein interactions or acting as signalling switches [ 1 , 4 ]. Because of their ability to regulate diverse signalling pathways, many pseudokinases are relevant to cancer progression, therapeutic response and the development of novel future therapies [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Structure vs. Function of TRIB1—Myeloid Neoplasms and Beyond

McMillan

Keeshan

Dunbier

et al. 2021

Cancers

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The Tribbles family of proteins—comprising TRIB1, TRIB2, TRIB3 and more distantly related STK40—play important, but distinct, roles in differentiation, development and oncogenesis. Of the four Tribbles proteins, TRIB1 has been most well characterised structurally and plays roles in diverse cancer types. The most well-understood role of TRIB1 is in acute myeloid leukaemia, where it can regulate C/EBP transcription factors and kinase pathways. Structure–function studies have uncovered conformational switching of TRIB1 from an inactive to an active state when it binds to C/EBPα. This conformational switching is centred on the active site of TRIB1, which appears to be accessible to small-molecule inhibitors in spite of its inability to bind ATP. Beyond myeloid neoplasms, TRIB1 plays diverse roles in signalling pathways with well-established roles in tumour progression. Thus, TRIB1 can affect both development and chemoresistance in leukaemia; glioma; and breast, lung and prostate cancers. The pervasive roles of TRIB1 and other Tribbles proteins across breast, prostate, lung and other cancer types, combined with small-molecule susceptibility shown by mechanistic studies, suggests an exciting potential for Tribbles as direct targets of small molecules or biomarkers to predict treatment response.

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“…While the biological functions of receptor tyrosine pseudokinases are incompletely understood, changes in their expression level are typically linked to proliferative diseases like cancer. Many pseudokinases exert their non-catalytic functions by allosterically regulating the kinase activity of their kinase-active counterparts [ 6 ]. For example, ErbB3/Her3, a pseudokinase of the EGFR family, promotes the tyrosine kinase activity of EGFR via heterodimerisation [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…For example, ErbB3/Her3, a pseudokinase of the EGFR family, promotes the tyrosine kinase activity of EGFR via heterodimerisation [ 7 ]. Other signalling functions have been proposed for pseudokinases, including nucleating assembly of signalling hubs [ 8 ], serving as molecular switches or integrators of signals [ 9 , 10 ], and as competitive signalling effectors [ 6 , 11 ]. Among the receptor tyrosine pseudokinases, PTK7, RYK and ROR1/2 were recently shown to exhibit conformational plasticity that could be modulated by conventional protein kinase inhibitors [ 12 , 13 ], raising the prospect that they may function as conformational switches.…”

Section: Introductionmentioning

confidence: 99%

“…Once phosphorylated, the EphB6-JM region provides a binding site for downstream SH2 domain-containing adaptor and signalling proteins, such as Abl, Src and Vav3, which facilitate signal transduction. Like ∼30% of pseudokinases [ 32 ], the pseudokinase domains of EphB6 and EphA10 exhibited the propensity to bind ATP, suggesting that a conformational switch might contribute to their regulation, as proposed for other nucleotide-binding pseudokinases [ 6 ]. In keeping with this propensity, both EphB6 and EphA10 could bind type I and type II kinase inhibitors, raising the possibility that either may be targetable by small molecule inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs

Liang

Roy

Horne

et al. 2021

Biochemical Journal

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EphB6 and EphA10 are two poorly characterised pseudokinase members of the Eph receptor family, which collectively serves as mediators of contact-dependent cell-cell communication to transmit extracellular cues into intracellular signals. As per their active counterparts, EphB6 and EphA10 deregulation is strongly linked to proliferative diseases. However, unlike active Eph receptors, whose catalytic activities are thought to initiate an intracellular signalling cascade, EphB6 and EphA10 are classified as catalytically-dead, raising the question of how non-catalytic functions contribute to Eph receptor signalling homeostasis. In this study, we have characterised the biochemical properties and topology of the EphB6 and EphA10 intracellular regions comprising the juxtamembrane region, pseudokinase and SAM domains. Using small-angle X-ray scattering and crosslinking-mass spectrometry, we observed high flexibility within their intracellular regions in solution and a propensity for interaction between the component domains. We identified tyrosines in the juxtamembrane region of EphB6 as EphB4 substrates, which can bind the SH2 domains of signalling effectors, including Abl, Src and Vav3, consistent with cellular roles in recruiting these proteins for downstream signaling. Furthermore, our finding that EphB6 and EphA10 can bind ATP and ATP-competitive small molecules raises the prospect that these pseudokinase domains could be pharmacologically-targeted to counter oncogenic signalling.

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There’s more to death than life: Noncatalytic functions in kinase and pseudokinase signaling

Cited by 70 publications

References 116 publications

SHED-Dependent Oncogenic Signaling of the PEAK3 Pseudo-Kinase

SHED-Dependent Oncogenic Signaling of the PEAK3 Pseudo-Kinase

Structure vs. Function of TRIB1—Myeloid Neoplasms and Beyond

The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs

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