LATS1/2 Kinases Review

LATS kinases belong to a family of proteins that, in mammals, are comprised of two isoforms, LATS1 and LATS2. Originally identified in Drosophila melanogaster as Warts kinase, LATS1 and LATS2 serine/threonine kinases have been shown to be tumour suppressors (Edwards and Munger 2004). The original homologue of LATS was described as the dlats/warts tumour suppressor in two independent screens in Drosophila (Justice et al. 1995, Xu et al. 1995). Dlats and warts encoded the same gene so in this thesis the original homologue of LATS is warts (wts). Homozygous loss of the warts gene in Drosophila formed greatly overgrown somatic cells which lead to the hypothesis that warts is a tumour suppressor and is important in regulating cell proliferation (Justice et al. 1995). LATS1 and 2, the human homologues of wts, were isolated and expressed in Drosophila that were homozygous mutants for wts. LATS1 is a core component of the MST2 pathway involved in the regulation of apoptosis or cell cycle regulation but can regulate biological functions independent of this pathway such as cell proliferation or cell migration (Visser and Yang 2010). The expression of LATS reversed the developmental defects of wts mutants and rescued the embryonic lethality (Tao et al. 1999). In mammals, LATS1 was identified as important in the regulation of cancer development, and studies have indicated that LATS1 expression is reduced in cancers. Mice which are ablated for the expression of LATS1 develop soft-tissue sarcomas and ovarian stromal cell tumours, demonstrating that LATS1 has an important role in regulating tumour development (St John et al. 1999). In humans, LATS1 down regulation was identified in a wide variety of cancers including breast cancer, tissue sarcoma, leukaemia and astrocytoma (Hisaoka et al. 2002, Jiang et al. 2006, Takahashi et al. 2005, Visser and Yang 2010).

LATS homology and structural domains

Warts was first identified in Drosophila but homologues were also identified in budding yeast (dbf2), fission yeast (orb6) and C. elegans (cLATS), which coded for putative Ser/Thr kinases (Tao et al. 1999, Xu et al. 1995, Yabuta et al. 2000). In humans, LATS Drosophila homologues were identified as NDR1/2 and LATS1/2 (Hori et al. 2000, Yabuta et al. 2000). Human LATS1 and wrt share an 86% homology in the C-terminal kinase but the overall homology is 42%. The AGC family of Ser/Thr kinases were identified based on the sequence alignments of their catalytic kinase domains from the proteins cAMP-dependent protein kinases (PKA), cGMP-dependent protein kinase (PKG) and protein kinase C (PKC) (Hanks and Hunter 1995). AGC kinases are activated by the phosphorylation of amino acid residues on the hydrophobic motif and on the activation loop located in the catalytic domain (Johnson et al. 1996).

LATS1 gene

LATS1 was mapped to the chromosome 6q24-51 chromosomal region (Nishiyama et al. 1999, Yabuta et al. 2000). Functional analysis has shown that LATS1 gene is mutated in about 1 to 2% of human cancers and decrease expression of LATS1 appears to be more common in cancers than actual somatic mutations (Yu et al. 2013). For example, in human astrocytoma, the promoter regions of LATS1 is hypermethylated as high as 70% and this hypermethylation is correlated with decreased levels of LATS1 mRNA transcripts. In human brain cell lines (U251) which have hypermethylation of LATS1 genes, treatment with the demethylation agent (5-aza-2-deoxycytidine) upregulated LATS1/2 expression (Jiang et al. 2006).

LATS1 kinase

LATS1 contains a variety of domains including its catalytic domain and motifs that facilitate protein-protein interactions. LATS1 contains a protein binding domain (PBD) that binds to several proteins including LIMK1, MOB1 and Zyxin (Bothos et al. 2005, Hirota et al. 2000, Yang et al. 2004). LATS1 contains two proline rich PPxY motif, which facilitate interactions with proteins that contain a WW motif such as YAP (Hao et al. 2008). LATS conserved domains (LCD) are found in LATS at the N-terminal region. Their functional significance is not fully understood but deletion of these regions inhibits LATS2 tumour suppressor activity in NIH3T3 cells (Li et al. 2003). Finally, LATS1 contains a P-stretch rich in proline residues that may facilitate protein-protein interactions but have not been described yet (Nishiyama et al. 1999, Yabuta et al. 2000).

LATS1 regulation of cellular responses

Most research on LATS1 functional activity has been focussed on its role in regulating the MST2 pathway, and specifically as a regulator of YAP (Wu et al. 2003). However, LATS1 was described to mediate other biological functions by regulation of different effectors, independent of the Hippo pathway. Overexpression of LATS1 can activate apoptosis and leads to cell cycle arrest at G2/M by reducing CDC2 kinase activity, therefore indicates that LATS1 is a tumour suppressor (Xia et al. 2002).ÿ Although the molecular mechanisms that are mediated by LATS1 are still poorly understood, the roles of LATS1 in regulating apoptosis, cell proliferation, cell cycle arrest and cytokinesis are well described. Interestingly, it is known that LATS1 negatively regulates cytokinesis by binding to LIMK1 that inhibits its activation by inhibiting cofilin phosphorylation, thereby preventing cytokinesis (Yang et al. 2004). Furthermore, LATS1 was described in the DNA damage response by interacting with CDK2, which results in the constraining of pS3291-BRCA2 and RAD51 nucleofilaments and leads to replication stalling (Pefani et al. 2014, Yang et al. 2004). In addition, LATS1 can activate YAP1 independent of MST2 through the activation of G-protein-coupled receptors (GPCR) (Yu et al. 2012). Moreover it has been shown that LATS1 can regulate effectors such as Omi/hTRA, resulting in the cell cycle halting at interphase (Kuninaka et al. 2007). Finally, LATS1 can induce apoptosis via the activation of Kras, which results in LATS1 binding to Mdm2 which inhibits the degradation of p53 (Matallanas et al. 2011). Different stimuli including mutant K-ras activation, genotoxic stress and activation of G-coupled receptors regulate different biological functions mediated by LATS1 (Matallanas et al. 2011, Pefani et al. 2014, Yu et al. 2012).

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