The characterisation of LATS2 kinase regulation in Hippo-YAP signalling.
Cell Signal
; 28(5): 488-497, 2016 May.
Article
em En
| MEDLINE
| ID: mdl-26898830
ABSTRACT
By controlling the YAP1 proto-oncoprotein Hippo signalling plays important roles in cancer-associated processes. Current evidence suggests that the Hippo kinases MST1/2 together with the MOB1 scaffold protein promote the formation of active MOB1/LATS complexes which phosphorylate and thereby inhibit YAP1. However, the regulatory mechanisms of MST1/2-MOB1-LATS signalling are currently underinvestigated. Therefore, we studied LATS2 variants carrying specific modifications that mimic gain or loss of phosphorylation and/or abolish MOB1/LATS2 interactions. We discovered that Ser872 T-loop and Thr1041 hydrophobic motif (HM) phosphorylation of LATS2 is essential for LATS2 activation. MST1/2 phosphorylate LATS2 on Thr1041, but not Ser872, while MOB1 binding to LATS2 supports both phosphorylation events. Significantly, LATS2-PIF, a LATS2 variant containing the PRK2 HM, acts as a hyperactive LATS2 kinase that efficiently phosphorylates YAP1 and inhibits the transcriptional co-activity of YAP1. This inhibitory function of LATS2-PIF is dependent on LATS2 kinase activity, while MOB1/LATS2 and YAP1/LATS2 complex formation is dispensable, suggesting that elevated LATS2 kinase activity can be sufficient to oppose YAP1. Taken together, our characterisation of LATS2 variants uncovers novel insights into the regulation of LATS kinases in Hippo signalling.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
/
Proteínas Serina-Treonina Quinases
/
Proteínas Supressoras de Tumor
/
Proteínas Adaptadoras de Transdução de Sinal
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Signal
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Reino Unido