Description
The Salvador/Warts/Hippo (Hippo) signaling pathway defines a novel signaling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis and cancer development in mammals. Events upstream of the core kinase cassette are less well characterized than some other parts of the pathway. KIBRA has been shown to function as an upstream member of the Hippo pathway in mammals by influencing the phosphorylation of LATS and YAP, but the functional consequences of these biochemical changes have not been previously addressed. We show that expression of FRMD6/Willin and KIBRA influence features of epithelial-to-mesenchymal transition (EMT), which are concomitant with decreased LATS and YAP phosphorylation, but not MST1/2 in the case of KIBRA. In addition, ectopic expression of both FRMD6/Willin and KIBRA antagonizes YAP via the serine 127 phosphorylation site. Reduced KIBRA expression in primary breast cancer specimens correlates with the recently described claudin-low subtype, an aggressive sub-group with epithelial-to-mesenchymal features and a poor clinical prognosis. Additionally, we are exploring scaffold proteins that influence the Hippo pathway core kinase cassette and also have a role in the function of cell surface receptors linked to Hippo signaling.The Salvador/Warts/Hippo (Hippo) signaling pathway defines a novel signaling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis and cancer development in mammals. Events upstream of the core kinase cassette are less well characterized than some other parts of the pathway. KIBRA has been shown to function as an upstream member of the Hippo pathway in mammals by influencing the phosphorylation of LATS and YAP, but the functional consequences of these biochemical changes have not been previously addressed. We show that expression of FRMD6/Willin and KIBRA influence features of epithelial-to-mesenchymal transition (EMT), which are concomitant with decreased LATS and YAP phosphorylation, but not MST1/2 in the case of KIBRA. In addition, ectopic expression of both FRMD6/Willin and KIBRA antagonizes YAP via the serine 127 phosphorylation site. Reduced KIBRA expression in primary breast cancer specimens correlates with the recently described claudin-low subtype, an aggressive sub-group with epithelial-to-mesenchymal features and a poor clinical prognosis. Additionally, we are exploring scaffold proteins that influence the Hippo pathway core kinase cassette and also have a role in the function of cell surface receptors linked to Hippo signaling.
| Period | 9 Jan 2015 |
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| Held at | National University of Singapore, Singapore |