癌症代表著複雜的自主系統，展示出在生長訊號方面的自給自足。自主生長是由於癌細胞能夠「分泌和感受」生長因子（GF）的能力所推動的：這是一種較不了解的現象。在本研究中，我們使用一種綜合計算和實驗方法，解析了一個反饋耦合的GTP酶迴路在分泌途徑中帶來的分泌耦合自主性的影響。當Ras超家族單聚物GTP酶Arf1和異三聚體GTP酶Giαβγ及其相應的GAP和GEF被GIV/Girdin耦合時，該迴路被組裝。這種蛋白質已知能夠在不同類型的癌症中推動侵略性特徵。迴路中的一個向前和兩個關鍵的負反饋迴路創建了閉環控制，允許兩個GTP酶互相協調，並將Arf1依賴的分泌所期望的開關狀態轉化為感受和分泌的意外的劑量反應對齊行為。這樣的行為轉化為細胞生存的自我維持，可通過刺激比例的分泌來實現。蛋白質體學研究和蛋白質-蛋白質相互作用網絡分析指出GF（例如表皮生長因子）是實現這種自我維持的關鍵刺激。研究結果突顯了癌細胞中兩個生物開關的增強耦合對於多尺度反饋控制實現生長因子分泌耦合自主性至關重要。© 2023作者。根據CC BY 4.0許可條款發布。

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.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.