FIGURE 1.

Co-regulation of Hippo and Hippo-like signaling pathways by Mob family proteins. Metazoans are equipped with two classes of NDR kinases, Tricornered- and Warts/LATS kinases. Mob family proteins have potential to balance the activities of these two classes of kinases in three ways (noted by balance icons). This pathway schematic is based on evidence from fly and mammalian literature, as discussed in the text. (A) As a STRIPAK component, Mob4/Phocein antagonizes Hippo/MST1/2 kinase activation. In balance with Salvador/Sav1 and Tao1, Mob4/Phocein determines Hippo/MST1/2 kinase activity. (B) The phosphorylation status of Class I Mob proteins alters their affinity for their NDR kinase partners. Non-phosphorylated Mob1 binds a human Tricornered-like kinase (STK38/STK38L) but not the Warts/LATS kinase (LATS1/2). Upon phosphorylation, Mob1 undergoes an activating allosteric transition that results in increased affinity for both Warts and Tricornered classes of NDR kinases. (C) Tricornered and Tricornered-like kinases bind both Class I and II Mob proteins. The effect of Mob2-binding to Tricornered-like kinases is unclear, with reports ascribing activating as well as inhibitory roles. Class II Mobs compete with Class I Mobs for binding to Tricornered-like kinases. In addition to Hippo, other STE20 kinases function upstream of NDR family kinases (Happyhour/MAP4K3, Misshapen/TNIK, GckIII/MST3/4), but it is not known whether they directly phosphorylate Mob family proteins.