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Interactome rewiring by phosphorylation and acetylation barcodes: implications in metabolic reprogramming in breast cancer

19th national competition for scientific and technical research

Intercellular Dialogue and Interactome: Pathological Implications

Senior Researcher : Federico Mayor Menéndez

Research Centre or Institution : Centro de Biología Molecular "Severo Ochoa". CSIC-Universidad Autónoma de Madrid

Abstract

Cancer is a complex process involving multiple and sequential changes in tumor cells as well as in their interactions with the tumor microenvironment. Metabolic reprogramming is considered one of the key events in cancer initiation and progression, by allowing adaptation to fluctuations in oxygen or nutrient availability. The interactome of certain signaling nodes can be switched in tumor contexts, so these proteins act as “onco-modulators” to strengthen tumor hallmarks. We propose that breast cancer cells undergo interconnected changes in the phosphorylation status of the multifunctional GRK2 kinase, the cytoplasmic deacetylase HDAC6 and the MDM2 oncoprotein, thus rewiring their interactome and leading to tumor progression.

Our results are consistent with the notion that modified GRK2 levels and phosphorylation “barcode” would rewire its interactome, switching the repertoire of GRK2 partners and altering key signaling modules, thus helping breast cancer cells to adapt to specific microenvironment and metabolic challenges in metastatic niches.

 We have uncovered a novel GRK2/HDAC6-governed breast cancer cell acetylome relevant in breast cancer cell invasion and identified Snail1 and the mRNA-binding protein HuR/ELAV1 as novel GRK2 substrates. Prior GRK2-S670 phosphorylation is required for phosphorylating HuR. The GRK2/HuR cascade would provide a link between relevant tumor-associated stresses (adrenergic, low oxygen) and the central metabolic and hypoxia modulator HIF-1α, likely contributing to rewire breast cancer cell networks, metabolism and secretome to promote organ-specific metastasis. We also find that GRK2-tyrosine phosphorylation status is relevant for crosstalk between key tumoral CXCR4/ACKR3-EGFR/GRK2/Lyn pathways related to cancer progression. Moreover, GRK2-mediated Mdm2 phosphorylation has specific impact in the global ubiquitome of breast cancer cells, and GRK2 dosage may modulate structural changes in breast tissue triggered by diet-induced obesity, a risk factor for breast cancer. Defining a GRK2/HDAC6/MDM2- dependent “metabolic and signaling signature” in breast tumors might help to identify potential targets for combination therapies.

 

Scientific Production
 
Magazine Articles 9
Communications at national conferences 5
Communications at international conferences 3

 

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