A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cells
Abstract 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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-03-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.202211127 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Lingxia Qiao |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-fa7b3bde97544f3e97560e5c2c0d0fc4 |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2023-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-fa7b3bde97544f3e97560e5c2c0d0fc42024-11-10T12:48:13ZengSpringer NatureMolecular Systems Biology1744-42922023-03-0119412710.15252/msb.202211127A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cellsLingxia Qiao0Saptarshi Sinha1Amer Ali Abd El‐Hafeez2I‐Chung Lo3Krishna K Midde4Tony Ngo5Nicolas Aznar6Inmaculada Lopez‐Sanchez7Vijay Gupta8Marilyn G Farquhar9Padmini Rangamani10Pradipta Ghosh11Department of Mechanical and Aerospace Engineering, Jacob's School of Engineering, University of California San DiegoDepartment of Cellular and Molecular Medicine, School of Medicine, University of California San DiegoDepartment of Cellular and Molecular Medicine, School of Medicine, University of California San DiegoDepartment of Cellular and Molecular Medicine, School of Medicine, University of California San DiegoDepartment of Cellular and Molecular Medicine, School of Medicine, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Science, University of California San DiegoDepartment of Cellular and Molecular Medicine, School of Medicine, University of California San DiegoDepartment of Cellular and Molecular Medicine, School of Medicine, University of California San DiegoDepartment of Cellular and Molecular Medicine, School of Medicine, University of California San DiegoDepartment of Cellular and Molecular Medicine, School of Medicine, University of California San DiegoDepartment of Mechanical and Aerospace Engineering, Jacob's School of Engineering, University of California San DiegoDepartment of Cellular and Molecular Medicine, School of Medicine, University of California San DiegoAbstract 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.https://doi.org/10.15252/msb.202211127cellular autonomydose–response alignment (DoRA)epidermal growth factor receptor (EGFR)G proteinsGolgi secretion |
| spellingShingle | 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 A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cells Molecular Systems Biology cellular autonomy dose–response alignment (DoRA) epidermal growth factor receptor (EGFR) G proteins Golgi secretion |
| title | A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cells |
| title_full | A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cells |
| title_fullStr | A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cells |
| title_full_unstemmed | A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cells |
| title_short | A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cells |
| title_sort | circuit for secretion coupled cellular autonomy in multicellular eukaryotic cells |
| topic | cellular autonomy dose–response alignment (DoRA) epidermal growth factor receptor (EGFR) G proteins Golgi secretion |
| url | https://doi.org/10.15252/msb.202211127 |
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