A non-canonical role for pyruvate kinase M2 as a functional modulator of Ca2+ signalling through IP3 receptors

Lavik, Andrew R.; McColl, Karen; Lemos, Fernanda O.; Kerkhofs, Martijn; Zhong, Fei; Harr, Michael W.; Schlatzer, Daniela; Hamada, Kozo; Mikoshiba, Katsuhiko; Crea, Francesco; Bultynck, Geert; Bootman, Martin D.; Parys, Jan B.; Distelhorst, Clark W.

doi:10.1016/j.bbamcr.2021.119206

Cited by 11 publications

(18 citation statements)

References 84 publications

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“…For example, CLL cells with high expression of Lck (Lck hi ) have increased proliferative capacity and survival vs Lck low cells [ 9 , 10 ]. While D5SD peptide does not physically interact with Lyn, it does bind other proteins such as PKM2 that interact with IP 3 R-3 [ 35 ], which could affect its cytotoxic potential in certain cell types. Importantly, we have shown that TAT-D5SD does not have cytotoxic activity in epithelial cells or fibroblasts; presumably this is because Lck is either not expressed or does not play a role in the survival of non-hematopoietic cells.…”

Section: Discussionmentioning

confidence: 99%

A Novel Peptide that Disrupts the Lck-IP3R Protein-Protein Interaction Induces Widespread Cell Death in Leukemia and Lymphoma

W. Harr,

Lavik,

McColl

et al. 2023

Arch Microbiol Immunology

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There is increasing evidence that the T-cell protein, Lck, is involved in the pathogenesis of chronic lymphocytic leukemia (CLL) as well as other leukemias and lymphomas. We previously discovered that Lck binds to domain 5 of inositol 1,4,5-trisphosphate receptors (IP 3 R) to regulate Ca 2+ homeostasis. Using bioinformatics, we targeted a region within domain 5 of IP 3 R-1 predicted to facilitate protein-protein interactions (PPIs). We generated a synthetic 21 amino acid peptide, KKRMDLVLELKNNASKLLLAI, which constitutes a domain 5 sub-domain (D5SD) of IP 3 R-1 that specifically binds Lck via its SH2 domain. With the addition of an HIV-TAT sequence to enable cell permeability of D5SD peptide, we observed wide-spread, Ca 2+ -dependent, cell killing of hematological cancer cells when the Lck-IP 3 R PPI was disrupted by TAT-D5SD. All cell lines and primary cells were sensitive to D5SD peptide, but malignant T-cells were less sensitive compared with B-cell or myeloid malignancies. Mining of RNA-seq data showed that LCK was expressed in primary diffuse large B-cell lymphoma (DLBCL) as well as acute myeloid leukemia (AML). In fact, LCK shows a similar pattern of expression as many well-characterized AML oncogenes and is part of a protein interactome that includes FLT3-ITD, Notch-1, and Kit. Consistent with these findings, our data suggest that the Lck-IP 3 R PPI may protect malignant hematopoietic cells from death. Importantly, TAT-D5SD showed no cytotoxicity in three different non-hematopoietic cell lines; thus its ability to induce cell death appears specific to hematopoietic cells. Together, these data show that a peptide designed to disrupt the Lck-IP 3 R PPI has a wide range of pre-clinical activity in leukemia and lymphoma.

show abstract

Section: Discussionmentioning

confidence: 99%

A Novel Peptide that Disrupts the Lck-IP3R Protein-Protein Interaction Induces Widespread Cell Death in Leukemia and Lymphoma

W. Harr,

Lavik,

McColl

et al. 2023

Arch Microbiol Immunology

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show abstract

“…For example, CLL cells with high expression of Lck (Lck hi ) have increased proliferative capacity and survival vs Lck low cells (9, 10). While D5SD peptide does not physically interact with Lyn, it does bind other proteins such as PKM2 that interact with IP 3 R-3 (35), which could affect its cytotoxic potential in certain cell types.…”

Section: Discussionmentioning

confidence: 99%

A novel peptide that disrupts the Lck-IP3R protein-protein interaction induces widespread cell death in leukemia and lymphoma

Harr

Lavik

McColl

et al. 2023

Preprint

Self Cite

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There is increasing evidence that the T-cell protein, Lck, is involved in the pathogenesis of chronic lymphocytic leukemia (CLL) as well as other leukemias and lymphomas. We previously discovered that Lck binds to domain 5 of inositol 1,4,5-trisphosphate receptors (IP3R) to regulate Ca2+ homeostasis. Using bioinformatics, we targeted a region within domain 5 of IP3R-1 predicted to facilitate protein-protein interactions (PPIs). We generated a synthetic 21 amino acid peptide, KKRMDLVLELKNNASKLLLAI, which constitutes a domain 5 sub-domain (D5SD) of IP3R-1 that specifically binds Lck via its SH2 domain. With the addition of an HIV-TAT sequence to enable cell permeability of D5SD peptide, we observed wide-spread, Ca2+-dependent, cell killing of hematological cancer cells when the Lck-IP3R PPI was disrupted by TAT-D5SD. All cell lines and primary cells were sensitive to D5SD peptide, but malignant T-cells were less sensitive compared with B-cell or myeloid malignancies. Mining of RNA-seq data showed that LCK was expressed in primary diffuse large B-cell lymphoma (DLBCL) as well as acute myeloid leukemia (AML). In fact, LCK shows a similar pattern of expression as many well-characterized AML oncogenes and is part of a protein interactome that includes FLT3-ITD, Notch-1, and Kit. Consistent with these findings, our data suggest that the Lck-IP3R PPI may protect malignant hematopoietic cells from death. Importantly, TAT-D5SD showed no cytotoxicity in three different non-hematopoietic cell lines; thus its ability to induce cell death appears specific to hematopoietic cells. Together, these data show that a peptide designed to disrupt the Lck-IP3R PPI has a wide range of pre-clinical activity in leukemia and lymphoma.

show abstract

“…More than a hundred proteins have been identified to interact with IP3Rs [14], including many known oncogenes and tumor suppressors that affect IP3R activity and consequently cell death or cell survival [220,221]. However, also other proteins can similarly affect IP3R function, including metabolic enzymes as hexokinase 2 [222] and pyruvate kinase M2 [223].…”

Section: Regulation Of Ca 2+ -Mediated Apoptosismentioning

confidence: 99%

The ER-mitochondria interface, where Ca2+ and cell death meet

et al. 2023

Self Cite

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A non-canonical role for pyruvate kinase M2 as a functional modulator of Ca2+ signalling through IP3 receptors

Cited by 11 publications

References 84 publications

A Novel Peptide that Disrupts the Lck-IP3R Protein-Protein Interaction Induces Widespread Cell Death in Leukemia and Lymphoma

A Novel Peptide that Disrupts the Lck-IP3R Protein-Protein Interaction Induces Widespread Cell Death in Leukemia and Lymphoma

A novel peptide that disrupts the Lck-IP3R protein-protein interaction induces widespread cell death in leukemia and lymphoma

The ER-mitochondria interface, where Ca2+ and cell death meet

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