TY - JOUR
T1 - KIBRA Exhibits MST-independent Functional Regulation of the Hippo Signaling Pathway in Mammals
AU - Moleirinho, Susan
AU - Chang, Nicole
AU - Sims, Andrew
AU - Tilston-Lunel, Andrew Martin
AU - Angus, Liselotte
AU - Steele, Andrew
AU - Boswell, Vaila
AU - Barnett, Susan
AU - Ormandy, Christopher
AU - Faratian, Dana
AU - Gunn-Moore, Frank J
AU - Reynolds, Paul Andrew
PY - 2013
Y1 - 2013
N2 - 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. The upstream regulation of this pathway has been less well defined than the core kinase cassette. KIBRA has been shown to function as an upstream member of the Hippo pathway by influencing the phosphorylation of LATS and YAP, but functional consequences of these biochemical changes have not been previously addressed. We show that in MCF10A cells, loss of KIBRA expression displays epithelial-to-mesenchymal transition (EMT) features, which are concomitant with decreased LATS and YAP phosphorylation, but not MST1/2. In addition, ectopic KIBRA expression antagonizes YAP via the serine 127 phosphorylation site and we show that KIBRA, Willin and Merlin differentially regulate genes controlled by YAP. Finally, reduced KIBRA expression in primary breast cancer specimens correlates with the recently described claudin-low subtype, an aggressive sub-group with EMT features and a poor prognosis.
AB - 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. The upstream regulation of this pathway has been less well defined than the core kinase cassette. KIBRA has been shown to function as an upstream member of the Hippo pathway by influencing the phosphorylation of LATS and YAP, but functional consequences of these biochemical changes have not been previously addressed. We show that in MCF10A cells, loss of KIBRA expression displays epithelial-to-mesenchymal transition (EMT) features, which are concomitant with decreased LATS and YAP phosphorylation, but not MST1/2. In addition, ectopic KIBRA expression antagonizes YAP via the serine 127 phosphorylation site and we show that KIBRA, Willin and Merlin differentially regulate genes controlled by YAP. Finally, reduced KIBRA expression in primary breast cancer specimens correlates with the recently described claudin-low subtype, an aggressive sub-group with EMT features and a poor prognosis.
U2 - 10.1038/onc.2012.196
DO - 10.1038/onc.2012.196
M3 - Article
SN - 0950-9232
VL - 32
SP - 1821
EP - 1830
JO - Oncogene
JF - Oncogene
IS - 14
ER -
