Structural highlights
Function
MOB1A_HUMAN Activator of LATS1/2 in the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. Stimulates the kinase activity of STK38 and STK38L. Acts cooperatively with STK3/MST2 to activate STK38.[1] [2] [3]
Publication Abstract from PubMed
The Mst-Lats kinase cascade is central to the Hippo tumor-suppressive pathway that controls organ size and tissue homeostasis. The adaptor protein Mob1 promotes Lats activation by Mst, but the mechanism remains unknown. Here, we show that human Mob1 binds to autophosphorylated docking motifs in active Mst2. This binding enables Mob1 phosphorylation by Mst2. Phosphorylated Mob1 undergoes conformational activation and binds to Lats1. We determine the crystal structures of phospho-Mst2-Mob1 and phospho-Mob1-Lats1 complexes, revealing the structural basis of both phosphorylation-dependent binding events. Further biochemical and functional analyses demonstrate that Mob1 mediates Lats1 activation through dynamic scaffolding and allosteric mechanisms. Thus, Mob1 acts as a phosphorylation-regulated coupler of kinase activation by virtue of its ability to engage multiple ligands. We propose that stepwise, phosphorylation-triggered docking interactions of nonkinase elements enhance the specificity and robustness of kinase signaling cascades.
Structural basis for Mob1-dependent activation of the core Mst-Lats kinase cascade in Hippo signaling.,Ni L, Zheng Y, Hara M, Pan D, Luo X Genes Dev. 2015 Jun 24. PMID:26108669[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bichsel SJ, Tamaskovic R, Stegert MR, Hemmings BA. Mechanism of activation of NDR (nuclear Dbf2-related) protein kinase by the hMOB1 protein. J Biol Chem. 2004 Aug 20;279(34):35228-35. Epub 2004 Jun 14. PMID:15197186 doi:10.1074/jbc.M404542200
- ↑ Hirabayashi S, Nakagawa K, Sumita K, Hidaka S, Kawai T, Ikeda M, Kawata A, Ohno K, Hata Y. Threonine 74 of MOB1 is a putative key phosphorylation site by MST2 to form the scaffold to activate nuclear Dbf2-related kinase 1. Oncogene. 2008 Jul 17;27(31):4281-92. doi: 10.1038/onc.2008.66. Epub 2008 Mar 24. PMID:18362890 doi:10.1038/onc.2008.66
- ↑ Chow A, Hao Y, Yang X. Molecular characterization of human homologs of yeast MOB1. Int J Cancer. 2010 May 1;126(9):2079-89. doi: 10.1002/ijc.24878. PMID:19739119 doi:10.1002/ijc.24878
- ↑ Ni L, Zheng Y, Hara M, Pan D, Luo X. Structural basis for Mob1-dependent activation of the core Mst-Lats kinase cascade in Hippo signaling. Genes Dev. 2015 Jun 24. PMID:26108669 doi:http://dx.doi.org/10.1101/gad.264929.115
