MOD_LATS_1

The NDR/LATS kinase constitute a subfamily of the AGC group of protein kinases found in metazoa, fungi and slime moulds (Avruch,2012). Members of the NDR/LATS kinases family have been implicated in a variety of biological processes ranging from cell division and morphology to apoptosis and tumor suppression (Zhao,2010). The mammalian genome encodes four members of the NDR/LATS family: NDR1, NDR2, LATS1 and LATS2. In S. cerevisiae, Dbf2p and Cbk1p have been identified as orthologous to the NDR/LATS kinases. The corresponding kinases in S. pombe are Orb6 and Sid2. In TAXON:7215 they are known as Tricornered and Warts/Lats. In C. elegans Sax1 and Lats are the NDR/LATS kinases (Cornils,2011). Due to the expansion of LATS kinase isoforms and the number of their interacting partners, the complexity and the functional diversity seems to be increased in higher eukaryotes.
LATS1/LATS2 are primarily considered as central players in the Hippo tumour suppressor pathway, however they also participate in a range of other signalling pathways. (Zhao,2010). The core of the Hippo pathway consists of Hpo, Wts, Sav and Mats. Hippo (Hpo) is a Ste20 family protein kinase that complexes with the regulatory scaffold protein Salvador (Sav). The Hpo/Sav complex then phosphorylates and activates Warts (Wts). Wts has an activating subunit Mats. The active Wts/Mats complex then in turn phosphorylates the transcriptional co-activators Yorkie (Yki) in flies, and YAP and TAZ in mammals. Phosphorylation of these transcriptional co-activators leads to their association with 14-3-3 family proteins, cytoplasmic retention and inactivation (Zhao,2007). In the presence of active CK1 kinase, LATS1/2 mediated phosphorylation of YAP also leads to the recruitment of the beta-TRCP SCF E3 ligase thereby triggering the subsequent proteasomal degradation of YAP (Zhao,2010). The LATS kinases prefer to phosphorylate a peptide sequence in which the target serine/threonine residue is preceded by positively charged residues. Some of the LATS substrate proteins possess multiple sites for phosphorylation, each matching the consensus sequence Hx[RK]xx[ST]. Although the consensus sequence is similar to other AGC kinases, the LATS kinases are the only family which requires histidine at -5 position.