Beta 1-integrin-c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes.
Beta 1-integrin-c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes.
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DOI：
10.1038/ncomms11942
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发表时间：
2016-06-23
影响因子：
16.6
通讯作者：
Kermorgant S
中科院分区：
文献类型：
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作者：
Barrow-McGee R;Kishi N;Joffre C;Ménard L;Hervieu A;Bakhouche BA;Noval AJ;Mai A;Guzmán C;Robbez-Masson L;Iturrioz X;Hulit J;Brennan CH;Hart IR;Parker PJ;Ivaska J;Kermorgant S
受体酪氨酸激酶（RTK）和整合素协同刺激细胞迁移和肿瘤转移。在这里，我们报告说，整合素的影响信号的RTK，c-Met，从细胞内，以促进锚定非依赖性细胞存活。因此，c-Met和β1-整联蛋白共同内化，并逐渐在LC 3B阳性的“自噬相关内膜”（ARE）上募集。在悬浮培养的细胞中，β1-整合素促进ARE上持续的c-Met依赖性ERK 1/2磷酸化。这种信号转导依赖于ATG 5和Beclin 1，而不依赖于ATG 13，表明ARE属于非经典的自噬通路。ARE上的这种β1-整联蛋白依赖性c-Met-持续信号传导支持体内锚定非依赖性细胞存活和生长、肿瘤发生、侵袭和肺定殖。RTK-整联蛋白合作已被假定发生在质膜上，需要整联蛋白“内-外”或“外-内”信号传导。我们的研究结果报告了一种新的整合素-RTK合作模式，我们称之为“内部信号”。除了粘附之外，靶向整合素信号传导可能与癌症治疗相关。 受体酪氨酸激酶（RTK）和整合素之间的协同信号传导被认为发生在细胞表面。在这里，作者表明β1整联蛋白影响RTK，c-Met的信号传导，从一个新的细胞内隔室，他们称之为自噬相关内膜。
Receptor tyrosine kinases (RTKs) and integrins cooperate to stimulate cell migration and tumour metastasis. Here we report that an integrin influences signalling of an RTK, c-Met, from inside the cell, to promote anchorage-independent cell survival. Thus, c-Met and β1-integrin co-internalize and become progressively recruited on LC3B-positive ‘autophagy-related endomembranes' (ARE). In cells growing in suspension, β1-integrin promotes sustained c-Met-dependent ERK1/2 phosphorylation on ARE. This signalling is dependent on ATG5 and Beclin1 but not on ATG13, suggesting ARE belong to a non-canonical autophagy pathway. This β1-integrin-dependent c-Met-sustained signalling on ARE supports anchorage-independent cell survival and growth, tumorigenesis, invasion and lung colonization in vivo. RTK–integrin cooperation has been assumed to occur at the plasma membrane requiring integrin ‘inside-out' or ‘outside-in' signalling. Our results report a novel mode of integrin–RTK cooperation, which we term ‘inside-in signalling'. Targeting integrin signalling in addition to adhesion may have relevance for cancer therapy. Cooperative signalling between receptor tyrosine kinases (RTKs) and integrins is thought to occur at the cell surface. Here the authors show that β1 integrin influences signalling of an RTK, c-Met, from a novel intracellular compartment they call autophagy-related endomembranes.