MOB control: reviewing a conserved family of kinase regulators

Abstract

The family of Mps One binder (MOB) co-activator proteins is highly conserved from yeast to man. At least two different MOB proteins have been identified in every eukaryote analysed to date. Initially, yeast genetics revealed essential roles for Mob1p and Mob2p in the regulation of mitotic exit and cell morphogenesis. Studies in flies then showed that dMOB1/MATS is a core component of Hippo signalling. Loss of dMOB1 resulted in increased cell proliferation and decreased cell death, suggesting that MOB1 acts as tumour suppressor protein. Recent work focused primarily on mammalian cells has shown how hMOB1 can regulate NDR/LATS kinases, a function that can to be counteracted by hMOB2. Here we summarise and discuss our current knowledge of this emerging protein family, with emphasis on subcellular localisation, protein-protein interactions and biological functions in apoptosis, mitosis, morphogenesis, cell proliferation and centrosome duplication.

Figure 1. Phylogenetic relationships within the MOB protein family

Top: Phylogenetic tree using Clustal W phylogenetic calculation based on the neighbour-joining method. Budding and fission yeast scMob1p and spMob1p, respectively, group together with dMOB1 and hMOB1A/B (MOB1 subgroup), while scMob2p and spMob2p fall into a group together with dMOB2 and hMOB2 (MOB2 subgroup). dMOB3 together with hMOB3A/B/C forms a third group (MOB3 subgroup). Bottom: Display of primary sequence identities within the MOB protein family. hMOB1 is closest related to scMob1p, spMob1p, and dMOB1 in the respective species. hMOB2 is not as well conserved as hMOB1, since it aligns similarly with several MOB proteins in yeast and flies. The MOB3 subgroup displays close identity between dMOB3 and hMOB3A/B/C.

Figure 2. MOB signalling in mitosis and morphogenesis in Saccharomyces cerevisiae

(A) Mob1p together with the Ste20-like kinase Cdc15p activates the Dbf2p NDR/LATS kinase. The Mob1p/Dbf2p complex phosphorylates the phosphatase Cdc14p, thereby triggering mitotic exit of yeast cells. (B) Mob2p cooperates with the Ste20-like kinase Kic1p to stimulate the Cbk1p NDR/LATS kinase. The Mob2p/Cbk1p complex targets Ace2p and other factors to regulate Ace2p activity and cellular morphogenesis (RAM). Of note, Mob1p functions in complex with Dbf2p and not Cbk1p, and Mob2p functions together with Cbk1p and not Dbf2p. Signalling components are not interchangeable. Ste20-like kinases are in yellow. NDR/LATS kinases are green, and MOB proteins are shown in red. Phosphorylations are indicated by “P” in blue.

Figure 3. MOB signalling in Drosophila melanogaster

dMOB1/MATS together with the Ste20-like kinase Hippo activates both NDR/LATS kinases, namely Trc and Warts. While the Trc branch is important for morphological changes such as outgrowth of epidermal hair and dendritic tiling in sensory neurons, the Warts branch is required for dendritic maintenance in sensory neurons, in addition to controlling the balance of cell proliferation and apoptosis as part of Hippo signalling. In Hippo signalling, the dMOB1/Warts complex phosphorylates the proto-oncogene Yki, which in turn inactivates the transcriptional co-activator Yki. Substrates of the dMOB1/Trc complex are unknown. dMOB2 might function together with Trc in controlling morphogenesis. The role of dMOB3 is not yet understood. Ste20-like kinases are in yellow. NDR/LATS kinases are green, and MOB proteins are shown in red, purple and light blue. Phosphorylations are indicated by “P” in blue.

Figure 4. MOB signalling in human cells

hMOB1 together with the Ste20-like kinases MST1/2 activates all four NDR/LATS kinases, namely NDR1/2 and LATS1/2. While the NDR branch is important for centrosome and apoptosis biology, the LATS branch is required for controlling cell proliferation and apoptosis as part of Hippo signalling. In mammalian Hippo signalling, the hMOB1/LATS complex phosphorylates the proto-oncogenes YAP and TAZ, which in turn inactivates these transcriptional co-activators. Substrates of the hMOB1/NDR complex in centrosome duplication and apoptosis signalling are unknown. hMOB2 counteracts hMOB1/NDR signalling by competing with hMOB1 for binding to NDR. Functions and binding partners of hMOB3A/B/C are currently unknown. Ste20-like kinases are in yellow. NDR/LATS kinases are green, and MOB proteins are shown in red, purple and light blue. Phosphorylations are indicated by “P” in blue.