title: The characterisation of LATS2 kinase regulation in Hippo-YAP signalling.
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.
authors.affiliation: Tumour Suppressor Signalling Network Laboratory, UCL Cancer Institute, University College London, WC1E 6BT London, United Kingdom.
authors.forename: Lily
authors.initials: L
authors.lastname: Hoa
authors.affiliation: Tumour Suppressor Signalling Network Laboratory, UCL Cancer Institute, University College London, WC1E 6BT London, United Kingdom.
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Kulaberoglu
authors.affiliation: Tumour Suppressor Signalling Network Laboratory, UCL Cancer Institute, University College London, WC1E 6BT London, United Kingdom.
authors.forename: Ramazan
authors.initials: R
authors.lastname: Gundogdu
authors.affiliation: Tumour Suppressor Signalling Network Laboratory, UCL Cancer Institute, University College London, WC1E 6BT London, United Kingdom.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Cook
authors.affiliation: Tumour Suppressor Signalling Network Laboratory, UCL Cancer Institute, University College London, WC1E 6BT London, United Kingdom.
authors.forename: Merdiye
authors.initials: M
authors.lastname: Mavis
authors.affiliation: Tumour Suppressor Signalling Network Laboratory, UCL Cancer Institute, University College London, WC1E 6BT London, United Kingdom.
authors.forename: Marta
authors.initials: M
authors.lastname: Gomez
authors.affiliation: Tumour Suppressor Signalling Network Laboratory, UCL Cancer Institute, University College London, WC1E 6BT London, United Kingdom.
authors.forename: Valenti
authors.initials: V
authors.lastname: Gomez
authors.affiliation: Tumour Suppressor Signalling Network Laboratory, UCL Cancer Institute, University College London, WC1E 6BT London, United Kingdom. Electronic address: a.hergovich@ucl.ac.uk.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hergovich
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C496256:MOB1A protein, human; C496255:MOB1B protein, human; C088374:YAP1 protein, human; C406449:LATS2 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases; C097835:STK3 protein, human
keywords: Hippo-YAP tumour suppressor pathway; Intracellular kinase signalling; Large tumour suppressor kinase; MOB proteins; STK3/4