PDF《Hippo pathway》

1 Department of Molecular Cell Biology, The Weizmann Institute of Science, POB 26,

234 Herzl St., Rehovot 7610001, Israel *Corresponding author: YAylon, Department of Molecular Cell Biology, The Weizmann Institute of Science, POB 26,

234 Herzl St., Rehovot 7610001, Israel;

Tel: +972

8 9342390;

Fax: +972

8 9346004;

E-mail: [email protected] Received 23.3.17;

revised 30.4.17;

accepted 15.5.17;

Edited by G Melino;

published online 23.6.17 Cell Death and Differentiation (2017) 24, 1488C1501 &

2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1350-9047/17 www.nature.com/cdd proteins are able to rescue the loss of Wts functions in Drosophila.11,12 As in other developmental pathways, complexity tends to increase over evolution. This is evidenced by the existence of additional components impacting the Hippo pathway, a diversity that might have been facilitated by duplication of the single ancestral LATS gene into two paralogs (coinciding with the duplication of other Hippo components, i.e., MST, TEAD and YAP) during deuterostome evolution.6 Genetic studies in mice have underscored the functional differences between the duplicated LATS kinases. Loss of Lats2 is embryonic lethal on or before embryonic day E12.5, and this lethality is postulated to result from aberrant proliferation, mitotic defects and accumulated genomic instability.13,14 In contrast, Lats1-null mice are viable. However, they suffer from developmental defects such as infertility, growth retardation, pituitary dysfunc- tion and lack of ductal structures in the mammary gland. In addition, Lats1 ? / ? mice are prone to spontaneous and oncogene-induced sarcomas.15 In this review, we examine the features of LATS1 and LATS2, some of which are redundant (presumably represent- ing a common primordial LATS function), and others distinct (presumably acquired in the course of evolutionary diversifica- tion). The common ability of both LATS kinases to repress YAP/TAZ has been studied extensively (reviewed recently in Zanconato et al.16 and Meng et al.17 ). Therefore we will focus mainly on LATS utilization of effectors other than YAP/TAZ, and the impact of those interactions on cell fate. Protein Structure and Post-Translational Modifications of LATS Kinases Human LATS1 and LATS2 are Ser/Thr kinases of the AGC subfamily, most closely related to the nuclear Dbf2-related kinases (NDR1/2).18 While LATS1 and LATS2 share extensive sequence similarity within their kinase domain (85% similarity) located at the C terminus of the proteins, the N terminus portion displays significantly lower conservation (Figure

1 and detailed in Table 1).19,20 Immediately carboxyterminal to the catalytic domain of both kinases is a hydrophobic motif;

this pattern is akin to other AGC kinases such as AKT, S6K1 and PKC.18 Within the lowly conserved amino (N) terminus, there are two stretches of conserved sequences (LCD1 and 2) that are required for proper LATS regulation and function.21,22 Also within the N terminus, both LATS1 and LATS2 harbor evolutionarily conserved ubiquitin-associated domains. Such domains are known to bind ubiquitinated proteins and may function in LATS activation.23 Interestingly, each of the kinases possesses unique features, which may facilitate different proteinCprotein interactions;

the N terminus of LATS1 contains a proline-rich domain,24 while a unique PAPA repeat is found in LATS2.20 Furthermore, LATS2 encodes one, and LATS1 encodes two, PPxY motifs;

these are essential for interaction with the WW hydrophobic pockets of YAP, TAZ and other Hippo pathway components.25 Superimposed on the amino-acid sequence is a combina- torial '