A possible new mechanism that controls the movement of STAT3 within cancer cells

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A possible new mechanism that controls the movement of STAT3 within cancer cells

Tuesday, 31.03.2020

STAT3 is a transcription factor constitutively activated in 70 % of solid tumors, where it is related to cancer cell proliferation and survival and cancer-associated inflammatory responses. Conversely, inactivating mutations of STAT3 cause hyper IgE syndrome and turn patients more prone to develop tumours. In order for STAT3 to activate the expression of cancer- and inflammation-related genes, it has to form pairs with other STAT3 molecules and move from the cytoplasm to the nucleus or the mitochondria. We have developed a system to visualize these phenomena in living cells. We combined STAT3 molecules with different modifications and observed that they are significantly more likely to change location within cancer cells than STAT3 pairs where the two molecules are equally modified. Some of the former -“asymmetric”- pairs also altered the proliferation of cancer cells, while the latter equally modified did not. These observations challenge the current implicit consensus that the two STAT3 molecules within a pair are virtually identical in all ways. From our point of view, a STAT3 pair could work with only one of the molecules being active, and this could have therapeutic implications for cancer and other STAT3-related pathologies. Although our system has several technical limitations, and therefore we must be cautious at interpreting these results, our observations could also be extended to other signaling processes, because the formation of dimers and protein modifications as the ones we describe are very common in nature.

 

Authors and Affiliations:

Ricardo Letra‐Vilela, 1 , 2 Beatriz Cardoso, 1 Catarina Silva‐Almeida, 1 Ana Maia Rocha, 1 Fernanda Murtinheira, 1 , 2 Joana Branco‐Santos, 1 Carmen Rodriguez, 3 Vanesa Martin, 3 Mariana Santa‐Marta, 1 and Federico Herrera 1 , 2

1 Cell Structure and Dynamics Laboratory, Instituto de Tecnologia Quimica e Biologica (ITQB‐NOVA), Universidade Nova de Lisboa, Oeiras Portugal,

2 Cell Structure and Dynamics Laboratory, Faculdade de Ciências, Universidade de Lisboa, Lisbon Portugal,

3 Instituto Universitario de Oncología del Principado de Asturias (IUOPA) and Departamento de Morfología y Biología Celular, Facultad de Medicina, University of Oviedo, Oviedo Spain,

 

Abstract:

Signal transducer and activator of transcription 3 (STAT3) is a ubiquitous and pleiotropic transcription factor that plays essential roles in normal development, immunity, response to tissue damage and cancer. We have developed a Venus‐STAT3 bimolecular fluorescence complementation assay that allows the visualization and study of STAT3 dimerization and protein‐protein interactions in living cells. Inactivating mutations on residues susceptible to post‐translational modifications (PTMs) (K49R, K140R, K685R, Y705F and S727A) changed significantly the intracellular distribution of unstimulated STAT3 dimers when the dimers were formed by STAT3 molecules that carried different mutations (ie they were “asymmetric”). Some of these asymmetric dimers changed the proliferation rate of HeLa cells. Our results indicate that asymmetric PTMs on STAT3 dimers could constitute a new level of regulation of STAT3 signaling. We put forward these observations as a working hypothesis, since confirming the existence of asymmetric STAT3 homodimers in nature is extremely difficult, and our own experimental setup has technical limitations that we discuss. However, if our hypothesis is confirmed, its conceptual implications go far beyond STAT3, and could advance our understanding and control of signaling pathways.

 

Journal: FASEB Bioadvances

 

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003655/