RRC ID 64284
Author Ikeuchi M, Yuki R, Saito Y, Nakayama Y.
Title The tumor suppressor LATS2 reduces v-Src-induced membrane blebs in a kinase activity-independent manner.
Journal FASEB J
Abstract When cells with excess DNA, such as tetraploid cells, undergo cell division, it can contribute to cellular transformation via asymmetrical chromosome segregation-generated genetic diversity. Cell cycle progression of tetraploid cells is suppressed by large tumor suppressor 2 (LATS2) kinase-induced inhibitory phosphorylation of the transcriptional coactivator Yes-associated protein (YAP). We recently reported that the oncogene v-Src induces tetraploidy and promotes cell cycle progression of tetraploid cells by suppressing LATS2 activity. We explore here the mechanism by which v-Src suppresses LATS2 activity and the role of LATS2 in v-Src-expressing cells. LATS2 was directly phosphorylated by v-Src and the proto-oncogene c-Src, resulting in decreased LATS2 kinase activity. This kinase-deficient LATS2 accumulated in a YAP transcriptional activity-dependent manner, and knockdown of either LATS2 or the LATS2-binding partner moesin-ezrin-radixin-like protein (Merlin) accelerated v-Src-induced membrane bleb formation. Upon v-Src expression, the interaction of Merlin with LATS2 was increased possibly due to a decrease in Merlin phosphorylation at Ser518, the dephosphorylation of which is required for the open conformation of Merlin and interaction with LATS2. LATS2 was colocalized with Merlin at the plasma membrane in a manner that depends on the Merlin-binding region of LATS2. The bleb formation in v-Src-expressing and LATS2-knockdown cells was rescued by the reexpression of wild-type or kinase-dead LATS2 but not the LATS2 mutant lacking the Merlin-binding region. These results suggest that the kinase-deficient LATS2 plays a role with Merlin at the plasma membrane in the maintenance of cortical rigidity in v-Src-expressing cells, which may cause tumor suppression.
Volume 35(1)
Pages e21242
Published 2021-1-1
DOI 10.1096/fj.202001909R
PMID 33368671
MeSH Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism Animals Cell Membrane Structures / enzymology* Cell Membrane Structures / genetics HCT116 Cells HT29 Cells HeLa Cells Humans Mice NIH 3T3 Cells Neurofibromin 2 / genetics Neurofibromin 2 / metabolism Oncogene Protein pp60(v-src) / genetics Oncogene Protein pp60(v-src) / metabolism* Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism* Proto-Oncogene Mas Transcription Factors / genetics Transcription Factors / metabolism Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism* YAP-Signaling Proteins
IF 4.966
DNA material pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)