Dataset Information

Glutamate as an extracellular signalling molecule in unicellular protists

ABSTRACT: Glutamate supplied to Phaeodactylum tricornutum at concentrations of 25 uM and 250 uM. Samples were taken 4 hours after glutamate addition.

INSTRUMENT(S):

ORGANISM(S): Phaeodactylum Tricornutum

SUBMITTER: Lucy Gorman

LAB HEAD: Glen Wheeler

PROVIDER: PXD074385 | Pride | 2026-05-28

REPOSITORIES: Pride

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Publications

Glutamate as an extracellular signalling molecule in unicellular protists.

Murphy Eleanor E Gorman Lucy L Helliwell Katherine K Wheeler Glen G

Current biology : CB 20260501 9

The amino acid L-glutamate plays an important role in cell-cell communication, acting as the primary neurotransmitter in the human brain. Glutamate also plays an important signalling role in land plants, enabling long-range signalling in response to wounding<sup>1</sup>. However, the role of glutamate as an extracellular signalling molecule in unicellular eukaryotes has received far less attention. We find that ionotropic glutamate receptors are widely distributed in unicellular eukaryotes, incl ...[more]

PMID: 42086029

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Project description:Acute myeloid leukaemia (AML) is an aggressive haematological malignancy characterised by the clonal proliferation of myeloid progenitor cells in the bone marrow and peripheral blood. Dysregulation of the Wnt/β-catenin pathway has been implicated in the establishment and maintenance of leukaemic stem cells in AML, where higher expression of β-catenin promotes clonogenic capacity, drug resistance and inferior survival. The finding that low levels of Wnt signalling are necessary to maintain normal haematopoiesis makes β-catenin an attractive therapeutic target, however drug design has been hampered by a poor understanding of its molecular interactions in leukaemia cells. To address this, we previously characterised the β-catenin interactome in myeloid cells and identified a plethora of novel interacting proteins. One such validated interactor was Target of EGR1 (TOE1), a 510-amino acid member of the Asp-Glu-Asp-Asp (DEDD) family of deadenylases with previously uncharacterised function in haematopoietic cells. The β-catenin:TOE1 interaction was detected in the nuclear and cytosolic compartments of myeloid cell lines and primary AML samples, and β-catenin knockdown via short hairpin RNA (shRNA) was found to promote the cytosolic stabilisation of TOE1. Furthermore, TOE1 levels were found to be overexpressed in primary AML blasts versus normal cord-blood derived CD34+ haematopoietic stem and progenitor cells (HSPCs), suggesting that TOE1 levels may be dysregulated in leukaemia. TOE1 depletion using shRNA abrogated Wnt signalling capacity (TCF/LEF activity) through suppression of the Wnt transcription factor lymphoid enhancing factor 1 (LEF-1), likely via post-transcriptional mechanisms. TOE1 shRNA further suppressed the proliferation and survival of myeloid leukaemia cell lines (HEL and OCI-AML2) and primary human CD34+ HSPC, however this could not be fully explained through LEF-1 alone, since OCI-AML2 do not express LEF-1. Therefore, to explore a more unifying mechanism mediating the growth promoting phenotype of TOE1 we performed tandem mass tag (TMT)-labelling coupled to mass spectrometry analysis in TOE1 deficient HEL and OCI-AML2 cells. From this analysis we identified validated p21 (RAC1) activated kinase 2 (PAK2) as a consistently downregulated target across both cell lines, and demonstrated PAK2 knockdown alone was sufficient to reduce the proliferation (but not survival) of AML cell lines. Finally, expression of ectopic PAK2 was able to partially rescue the suppressed proliferation mediated by TOE1 depletion in myeloid cell lines, and primary human CD34+ HSPC. In summary, these data reveal TOE1 as novel interacting partner for β-catenin in haematological cells capable of modulating Wnt signalling output via LEF-1, and as a novel mediator of growth and survival in human HSPC and AML cells partly through PAK2 regulation.

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