The tumor suppressor LATS2 reduces v-Src-induced membrane blebs in a kinase activity-independent manner.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Cell Membrane Structures
/ enzymology
HCT116 Cells
HT29 Cells
HeLa Cells
Humans
Mice
NIH 3T3 Cells
Neurofibromin 2
/ genetics
Oncogene Protein pp60(v-src)
/ genetics
Protein Serine-Threonine Kinases
/ genetics
Proto-Oncogene Mas
Transcription Factors
/ genetics
Tumor Suppressor Proteins
/ genetics
YAP-Signaling Proteins
Hippo pathway
LATS2
Merlin
bleb
v-Src
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
14
08
2020
revised:
05
11
2020
accepted:
19
11
2020
entrez:
28
12
2020
pubmed:
29
12
2020
medline:
16
6
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33368671
doi: 10.1096/fj.202001909R
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
MAS1 protein, human
0
Neurofibromin 2
0
Nf2 protein, mouse
0
Proto-Oncogene Mas
0
Transcription Factors
0
Tumor Suppressor Proteins
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Yap1 protein, mouse
0
LATS2 protein, human
EC 2.7.1.11
Oncogene Protein pp60(v-src)
EC 2.7.10.2
LATS2 protein, mouse
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e21242Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
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