Illuminating histidine phosphorylation in the pancreatic tumor microenvironment

Hunter, Tony; Wahl, Geoffrey M.; Lytle, Nikki K.; DelGiorno, Kathleen E.; Shi, Yu; Kaech, Susan M.; Naeem, Razia; Luhtala, Natalie; Hollingsworth, Michael A.

doi:10.1101/2022.09.15.508158

Cited by 3 publications

(1 citation statement)

References 97 publications

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“…However, LHPP protein levels in these cancer types have not been confirmed in cancer cell lines, mouse models, or patient samples, and further work would be required to determine whether LHPP might have a tumor-promoting role in these cancers. In addition, LHPP levels were higher in the tumor cells compared to normal tissues in a mouse PDAC model (44), suggesting a tumor-promoting role for LHPP in this cancer type, in contrast to prior reports for PDAC (20,45).…”

Section: Discussioncontrasting

confidence: 82%

LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment

Reina,

Vallmajo-Martin,

Ning

et al. 2024

Preprint

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Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic form of breast cancer that lacks an effective targeted therapy. To identify new therapeutic targets, we investigated the phosphohistidine phosphatase, LHPP, which has been implicated in the development of several types of cancer. However, the full significance of LHPP in cancer progression remains unclear due to our limited understanding of its molecular mechanism. We found that levels of the LHPP phosphohistidine phosphatase were significantly increased in human breast cancer patients compared to normal adjacent tissues, with the highest levels in the TNBC subtype. When LHPP was knocked out in the MDA-MB-231 human TNBC cell line, cell proliferation, wound healing capacity, and invasion were significantly reduced. However, LHPP knockout in TNBC cells did not affect the phosphohistidine protein levels. Interestingly, LHPP knockout in MDA-MB-231 cells delayed tumor growth and reduced metastasis when orthotopically transplanted into mouse mammary glands. To investigate LHPP's role in breast cancer progression, we used next-generation sequencing and proximity-labeling proteomics, and found that LHPP regulates gene expression in chemokine-mediated signaling and actin cytoskeleton organization. Depletion of LHPP reduced the presence of tumor-infiltrating macrophages in mouse xenografts. Our results uncover a new tumor promoter role for LHPP phosphohistidine phosphatase in TNBC and suggest that targeting LHPP phosphatase could be a potential therapeutic strategy for TNBC.

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Section: Discussioncontrasting

confidence: 82%

LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment

Reina,

Vallmajo-Martin,

Ning

et al. 2024

Preprint

Self Cite

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PRUNE1 and NME/NDPK family proteins influence energy metabolism and signaling in cancer metastases

Ferrucci,

Lomada,

Wieland

et al. 2024

Cancer Metastasis Rev

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We describe here the molecular basis of the complex formation of PRUNE1 with the tumor metastasis suppressors NME1 and NME2, two isoforms appertaining to the nucleoside diphosphate kinase (NDPK) enzyme family, and how this complex regulates signaling the immune system and energy metabolism, thereby shaping the tumor microenvironment (TME). Disrupting the interaction between NME1/2 and PRUNE1, as suggested, holds the potential to be an excellent therapeutic target for the treatment of cancer and the inhibition of metastasis dissemination. Furthermore, we postulate an interaction and regulation of the other Class I NME proteins, NME3 and NME4 proteins, with PRUNE1 and discuss potential functions. Class I NME1–4 proteins are NTP/NDP transphosphorylases required for balancing the intracellular pools of nucleotide diphosphates and triphosphates. They regulate different cellular functions by interacting with a large variety of other proteins, and in cancer and metastasis processes, they can exert pro- and anti-oncogenic properties depending on the cellular context. In this review, we therefore additionally discuss general aspects of class1 NME and PRUNE1 molecular structures as well as their posttranslational modifications and subcellular localization. The current knowledge on the contributions of PRUNE1 as well as NME proteins to signaling cascades is summarized with a special regard to cancer and metastasis.

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Histidine Phosphorylation: Protein Kinases and Phosphatases

Ning,

Sala,

Reina

et al. 2024

IJMS

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Phosphohistidine (pHis) is a reversible protein post-translational modification (PTM) that is currently poorly understood. The P-N bond in pHis is heat and acid-sensitive, making it more challenging to study than the canonical phosphoamino acids pSer, pThr, and pTyr. As advancements in the development of tools to study pHis have been made, the roles of pHis in cells are slowly being revealed. To date, a handful of enzymes responsible for controlling this modification have been identified, including the histidine kinases NME1 and NME2, as well as the phosphohistidine phosphatases PHPT1, LHPP, and PGAM5. These tools have also identified the substrates of these enzymes, granting new insights into previously unknown regulatory mechanisms. Here, we discuss the cellular function of pHis and how it is regulated on known pHis-containing proteins, as well as cellular mechanisms that regulate the activity of the pHis kinases and phosphatases themselves. We further discuss the role of the pHis kinases and phosphatases as potential tumor promoters or suppressors. Finally, we give an overview of various tools and methods currently used to study pHis biology. Given their breadth of functions, unraveling the role of pHis in mammalian systems promises radical new insights into existing and unexplored areas of cell biology.

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Illuminating histidine phosphorylation in the pancreatic tumor microenvironment

Cited by 3 publications

References 97 publications

LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment

LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment

PRUNE1 and NME/NDPK family proteins influence energy metabolism and signaling in cancer metastases

Histidine Phosphorylation: Protein Kinases and Phosphatases

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