Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis.
Cell attachment to the extracellular matrix (ECM) is crucial to cell physiology such as polarity, motility, and proliferation. In normal cells, loss of attachment to the ECM induces a specific type of apoptosis, termed anoikis. Resistance to anoikis in cancer cells promotes their survival in circulation and dispersion to distant anatomic sites, leading to tumor metastasis. The Yes-associated protein (YAP) transcription coactivator is a human oncogene and a key regulator of organ size. The Hippo tumor suppressor pathway phosphorylates and inhibits YAP. However, little is known about the signals that regulate the Hippo pathway. Here we report that through cytoskeleton reorganization, cell detachment activates the Hippo pathway kinases Lats1/2 and leads to YAP phosphorylation and inhibition. The detachment-induced YAP inactivation is required for anoikis in nontransformed cells, whereas in cancer cells with deregulation of the Hippo pathway, knockdown of YAP and TAZ restores anoikis. Furthermore, we provided evidence that Lats1/2 expression level is indeed significantly down-regulated in metastatic prostate cancer. Our findings provide a novel connection between cell attachment and anoikis through the Hippo pathway and have important implications in cancer therapeutics.
Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.
Bin
B
Zhao
Li
L
Li
Lloyd
L
Wang
Cun-Yu
CY
Wang
Jindan
J
Yu
Kun-Liang
KL
Guan
D000818:Animals; D023102:Anoikis / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002477:Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D022001:Focal Adhesions / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D014157:Transcription Factors / Q000378:metabolism
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D017346:Protein Serine-Threonine Kinases