Signaling by Hippo

Cytosolic caspase 3 cleaves p-STK3 (p-MST2) to yield an active animo-terminal fragment (p-STK3/N) and a carboxy-terminal fragment (p-STK3/C) (Lee et al. 2001). The association of p-STK3 (p-MST2) with other proteins at the time of its cleavage by caspase has not been studied experimentally. Here, it is inferred to be dimerized and in a complex with SAV1 because that is the form of the molecule that becomes phosphorylated and phosphorylation appears normally to precede caspase cleavage. The effect of the cleavage is to increase the kinase activity of p-STK3 (p-MST2).


Signaling by Hippo ↗ Stable identifier: R-HSA-2028269
Compartments: cytosol Human Hippo signaling is a network of reactions that regulates cell proliferation and apoptosis, centered on a three-step kinase cascade. The cascade was discovered by analysis of Drosophila mutations that lead to tissue overgrowth, and human homologues of its components have since been identified and characterized at a molecular level. Data from studies of mice carrying knockout mutant alleles of the genes as well as from studies of somatic mutations in these genes in human tumors are consistent with the conclusion that in mammals, as in flies, the Hippo cascade is required for normal regulation of cell proliferation and defects in the pathway are associated with cell overgrowth and tumorigenesis (Oh and Irvine 2010;Pan 2010;Zhao et al. 2010). This group of reactions is also notable for its abundance of protein:protein interactions mediated by WW domains and PPxY sequence motifs (Sudol and Harvey 2010).
There are two human homologues of each of the three Drosophila kinases, whose functions are well con- In their unphosphorylated states, YAP1 and WWTR1 freely enter the nucleus and function as transcriptional co-activators. In their phosphorylated states, however, YAP1 and WWTR1 are instead bound by 14-3-3 proteins, YWHAB and YWHAE respectively, and sequestered in the cytosol.
Several accessory proteins are required for the three-step kinase cascade to function. STK3 (MST2) and STK4 (MST1) each form a complex with SAV1 (homologue of Drosophila Salvador), and LATS1 and LATS2 form complexes with MOB1A and MOB1B (homologues of Drosophila Mats).
In Drosophila a complex of three proteins, Kibra, Expanded, and Merlin, can trigger the Hippo cascade.
A human homologue of Kibra, WWC1, has been identified and indirect evidence suggests that it can regulate the human Hippo pathway (Xiao et al. 2011). A molecular mechanism for this interaction has not https://reactome.org yet been worked out and the molecular steps that trigger the Hippo kinase cascade in humans are unknown.
Four additional processes related to human Hippo signaling, although incompletely characterized, have been described in sufficient detail to allow their annotation. All are of physiological interest as they are likely to be parts of mechanisms by which Hippo signaling is modulated or functionally linked to other signaling processes. First, the caspase 3 protease cleaves STK3 (MST2) and STK4 (MST1), releasing inhibitory carboxyterminal domains in each case, leading to increased kinase activity and YAP1 / TAZ phosphorylation (Lee et al. 2001). Second, cytosolic AMOT (angiomotin) proteins can bind YAP1 and WWTR1 (TAZ) in their unphosphorylated states, a process that may provide a Hippo-independent mechanism to down-regulate the activities of these proteins (Chan et al. 2011). Third, WWTR1 (TAZ) and YAP1 bind ZO-1 and 2 proteins (Remue et al. 2010;Oka et al. 2010). Fourth, phosphorylated WWTR1 (TAZ) binds and sequesters DVL2, providing a molecular link between Hippo and Wnt signaling (Varelas et al. 2010). Lei, Q., Guan, KL., Li, L., Zhao, B. (2010). The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version.   Here, it is inferred to be dimerized and in a complex with SAV1 because that is the form of the molecule that becomes phosphorylated and phosphorylation appears normally to precede caspase cleavage. The effect of the cleavage is to increase the kinase activity of p-STK4 (p-MST1).

Literature references
Preceded by: Phosphorylation of STK4 (MST1) and SAV1 by STK4     AMOTL2 -WWTR1 binding has not been studied but is inferred to occur from the presence of key binding sequence motifs in AMOTL2 protein and from its known binding activity with YAP1, a WWTR1 homolog. These interactions are not dependent on WWTR1 phosphorylation and may thus be a means of negatively regulating WWTR1 activity in addition to the ones dependent on Hippo pathway-dependent phosphorylation. AMOT -WWTR1 binding is dependent on sequence motifs in the amino terminal portions of the AMOT proteins (and that are absent from the AMOT 80 KDa isoform) (Chan et al. 2011).