highly conserved Thr117 by Akt (protein kinase B), blocking autophosphorylation of Thr180, MST2 cleavage, kinase activity, and translocation to the nucleus. MST2 substrates In the mammalian Hippo signaling pathway, MST2, along with its homolog MST1, serves as an upstream kinase whose catalytic activity is responsible for downstream events leading to downregulation of proliferation-associated genes and increased transcription of proapoptotic genes. When MST2 binds to SAV1 through its SARAH domain, MST2 phosphorylates LATS1/LATS2 with the help of SAV1, MOB1A/MOB1B, and Merlin (protein). In turn, LATS1/LATS2 phosphorylates and inhibits YAP1, preventing its movement into the nucleus and activation of transcription of pro-proliferative, anti-apoptotic and migration-associated genes. In the cytoplasm, YAP1 is marked for degradation by the SCF complex. Additionally, MST2 phosphorylates transcription factors in the FOXO (Forkhead box O) family, which diffuse into the nucleus and activate transcription of pro-apoptotic genes. Disease Relevance In many types of cancers, the proto-oncogene c-Raf binds to the SARAH domain of MST2 and prevents RASSF1A-mediated MST2 dimerization and subsequent downstream pro-apoptotic signaling. Research has shown that in cells with loss of PTEN (gene), a tumor suppressor that is frequently mutated in cancers, Akt activity is upregulated, resulting in increased MST2 inactivation and undesirable cell proliferation. References Further reading External links