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  • A circuit for secretion-coupled cellular autonomy in multicellular eukaryotic cells.

A circuit for secretion-coupled cellular autonomy in multicellular eukaryotic cells.

Molecular systems biology (2023-03-02)
Lingxia Qiao, Saptarshi Sinha, Amer Ali Abd El-Hafeez, I-Chung Lo, Krishna K Midde, Tony Ngo, Nicolas Aznar, Inmaculada Lopez-Sanchez, Vijay Gupta, Marilyn G Farquhar, Padmini Rangamani, Pradipta Ghosh
摘要

Cancers represent complex autonomous systems, displaying self-sufficiency in growth signaling. Autonomous growth is fueled by a cancer cell's ability to "secrete-and-sense" growth factors (GFs): a poorly understood phenomenon. Using an integrated computational and experimental approach, here we dissect the impact of a feedback-coupled GTPase circuit within the secretory pathway that imparts secretion-coupled autonomy. The circuit is assembled when the Ras-superfamily monomeric GTPase Arf1, and the heterotrimeric GTPase Giαβγ and their corresponding GAPs and GEFs are coupled by GIV/Girdin, a protein that is known to fuel aggressive traits in diverse cancers. One forward and two key negative feedback loops within the circuit create closed-loop control, allow the two GTPases to coregulate each other, and convert the expected switch-like behavior of Arf1-dependent secretion into an unexpected dose-response alignment behavior of sensing and secretion. Such behavior translates into cell survival that is self-sustained by stimulus-proportionate secretion. Proteomic studies and protein-protein interaction network analyses pinpoint GFs (e.g., the epidermal GF) as key stimuli for such self-sustenance. Findings highlight how the enhanced coupling of two biological switches in cancer cells is critical for multiscale feedback control to achieve secretion-coupled autonomy of growth factors.

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Sigma-Aldrich
磷酸酶抑制剂混合物2, aqueous solution (dark coloration may develop upon storage, which does not affect the activity)
Sigma-Aldrich
磷酸酶抑制剂混合物3, DMSO solution