The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1.
Originally identified in Drosophila melanogaster, the Warts(Wts)/Lats protein kinase has been proposed to function with two other Drosophila proteins, Hippo (Hpo) and Salvador (Sav), in the regulation of cell cycle exit and apoptosis. In mammals, two candidate Warts/Lats homologs, termed Lats1 and Lats2, have been described, and the targeted disruption of LATS1 in mice increases tumor formation. Little, however, is known about the function and regulation of human Lats kinases. Here we report that human Mst2, a STE20-family member and purported Hpo ortholog, phosphorylates and activates both Lats1 and Lats2. Deletion analysis revealed that regulation of Lats1 occurs through the C-terminal, catalytic domain. Within this domain, two regulatory phosphorylation sites were identified by mass spectrometry. These sites, S909 in the activation loop and T1079 within a hydrophobic motif, have been highly conserved during evolution. Moreover, a direct interaction was observed between Mst2 and hWW45, a putative ortholog of Drosophila Sav. These results indicate that Mst2-like kinases regulate Lats kinase activities in an evolutionarily conserved regulatory pathway. Although the function of this pathway remains poorly understood in mammals, it is intriguing that, in Drosophila, it has been linked to development and tissue homeostasis.
Chan
Eunice H Y
EH
Department of Cell Biology, Max Planck Institute for Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
Nousiainen
Marjaana
M
Chalamalasetty
Ravindra B
RB
Schäfer
Anja
A
Nigg
Erich A
EA
Silljé
Herman H W
HH
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004331:Drosophila melanogaster; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006801:Humans; D007668:Kidney; D010446:Peptide Fragments / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000090742:Serine-Threonine Kinase 3; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000099317:Hippo Kinases
D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; D025521:Tumor Suppressor Proteins; C092745:LATS1 protein, human; C406449:LATS2 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases