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Phosphohistidine signaling promotes FAK-RB1 interaction and growth factor-independent proliferation of esophageal squamous cell carcinoma

Oncogene volume 42, pages 449–460 (2023)Cite this article

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Abstract

Current clinical therapies targeting receptor tyrosine kinases including focal adhesion kinase (FAK) have had limited or no effect on esophageal squamous cell carcinoma (ESCC). Unlike esophageal adenocarcinomas, ESCC acquire glucose in excess of their anabolic need. We recently reported that glucose-induced growth factor-independent proliferation requires the phosphorylation of FAKHis58. Here, we confirm His58 phosphorylation in FAK immunoprecipitates of glucose-stimulated, serum-starved ESCC cells using antibodies specific for 3-phosphohistidine and mass spectrometry. We also confirm a role for the histidine kinase, NME1, in glucose-induced FAKpoHis58 and ESCC cell proliferation, correlating with increased levels of NME1 in ESCC tumors versus normal esophageal tissues. Unbiased screening identified glucose-induced retinoblastoma transcriptional corepressor 1 (RB1) binding to FAK, mediated through a “LxCxE” RB1-binding motif in FAK’s FERM domain. Importantly, in the absence of growth factors, glucose increased FAK scaffolding of RB1 in the cytoplasm, correlating with increased ESCC G1→S phase transition. Our data strongly suggest that this glucose-mediated mitogenic pathway is novel and represents a unique targetable opportunity in ESCC.

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Fig. 1: Glucose (Glc) induces G1 to S/G2/M phase transition of ESCC cells.
Fig. 2: Glucose (Glc) induces histidine phosphorylation of FAK and proliferation.
Fig. 3: Glucose (Glc) promotes NME1 modulation of pHis-FAK and proliferation.
Fig. 4: Glucose (Glc) modulates PP2A, pHis and proliferation.
Fig. 5: Glucose (Glc) promotes FAK-RB1 interaction.
Fig. 6: NME1 expression and FAK-RB1 interaction are increased in ESCC.
Fig. 7: Glucose-induced NME1/PP2A-pHis-FAK-RB1 signaling and tumor growth.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Funding

Roswell Park Comprehensive Cancer Center Alliance Foundation Grant (SH and JZ).

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Authors and Affiliations

  1. Bioscience Research Center, Chi University, Reddick, FL, 32686, USA

    Jianliang Zhang

  2. Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Irwin H. Gelman

  3. University at Buffalo, Department of Pharmaceutical Sciences, Buffalo, NY, 14215, USA

    Jun Qu

  4. Mount Sinai Cancer Center, Mount Sinai Medical Center, Miami Beach, FL, 33140, USA

    Steven N. Hochwald

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Contributions

JZ: Designed and performed experiments and prepared the manuscript. IG: TCGA database search and analysis, study design, data interpretation and critical revision of manuscript. JQ: Designed MS study and interpreted MS results. SH: Study design, data analysis/interpretation and manuscript preparation.

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Correspondence to Steven N. Hochwald.

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Zhang, J., Gelman, I.H., Qu, J. et al. Phosphohistidine signaling promotes FAK-RB1 interaction and growth factor-independent proliferation of esophageal squamous cell carcinoma. Oncogene 42, 449–460 (2023). https://doi.org/10.1038/s41388-022-02568-4

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