Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.
Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada H3A 1A3.
Nat Commun. 2013;4:2976. doi: 10.1038/ncomms3976.
One of the hallmarks of cancers is the silencing of tumour suppressor genes and pathways. The Hippo tumour suppressor pathway is inactivated in many types of cancers, leading to tumour progression and metastasis. However, the mechanisms of pathway inactivation in tumours remain unclear. Here we demonstrate that integrin-linked kinase (ILK) plays a critical role in the suppression of the Hippo pathway via phospho-inhibition of MYPT1-PP1, leading to inactivation of Merlin. Inhibition of ILK in breast, prostate and colon tumour cells results in the activation of the Hippo pathway components MST1 and LATS1 with concomitant inactivation of YAP/TAZ (Yes-associated protein/transcriptional co-activator with PDZ-binding motif) transcriptional co-activators and TEAD-mediated transcription. Genetic deletion of ILK suppresses ErbB2-driven YAP/TAZ activation in mammary tumours, and its pharmacological inhibition suppresses YAP activation and tumour growth in vivo. Our data demonstrate a role for ILK as a multiple receptor proximal regulator of Hippo tumour suppressor pathway and as a cancer therapeutic target.
癌症的一个特征是肿瘤抑制基因和途径的沉默。Hippo 肿瘤抑制途径在许多类型的癌症中失活，导致肿瘤的进展和转移。然而，肿瘤中途径失活的机制仍不清楚。在这里，我们证明整合素连接激酶（ILK）通过磷酸化抑制 MYPT1-PP1 在 Merlin 的抑制中起关键作用，导致 Merlin 的失活。在乳腺、前列腺和结肠肿瘤细胞中抑制 ILK 会导致 Hippo 途径成分 MST1 和 LATS1 的激活，同时伴随 YAP/TAZ（Yes 相关蛋白/转录共激活因子与 PDZ 结合基序）转录共激活因子和 TEAD 介导的转录的失活。ILK 的基因缺失抑制了 ErbB2 驱动的 YAP/TAZ 在乳腺肿瘤中的激活，其药理学抑制抑制了 YAP 的激活和体内肿瘤的生长。我们的数据表明，ILK 作为 Hippo 肿瘤抑制途径的多个受体近端调节剂和癌症治疗靶点发挥作用。
