5loh
Kinase domain of human Greatwall
Structural highlights
DiseaseGWL_HUMAN Autosomal thrombocytopenia with normal platelets. The disease is caused by mutations affecting the gene represented in this entry. FunctionGWL_HUMAN Serine/threonine kinase that plays a key role in M phase by acting as a regulator of mitosis entry and maintenance. Acts by promoting the inactivation of protein phosphatase 2A (PP2A) during M phase: does not directly inhibit PP2A but acts by mediating phosphorylation and subsequent activation of ARPP19 and ENSA at 'Ser-62' and 'Ser-67', respectively. ARPP19 and ENSA are phosphatase inhibitors that specifically inhibit the PPP2R2D (PR55-delta) subunit of PP2A. Inactivation of PP2A during M phase is essential to keep cyclin-B1-CDK1 activity high. Following DNA damage, it is also involved in checkpoint recovery by being inhibited. Phosphorylates histone protein in vitro; however such activity is unsure in vivo. May be involved in megakaryocyte differentiation.[1] [2] [3] [4] [5] Publication Abstract from PubMedMASTL (microtubule-associated serine/threonine kinase-like), more commonly known as Greatwall (GWL), has been proposed as a novel cancer therapy target. GWL plays a crucial role in mitotic progression, via its known substrates ENSA/ARPP19, which when phosphorylated inactivate PP2A/B55 phosphatase. When over-expressed in breast cancer, GWL induces oncogenic properties such as transformation and invasiveness. Conversely, down-regulation of GWL selectively sensitises tumour cells to chemotherapy. Here we describe the first structure of the GWL minimal kinase domain and development of a small-molecule inhibitor GKI-1 (Greatwall Kinase Inhibitor-1). In vitro, GKI-1 inhibits full-length human GWL, and shows cellular efficacy. Treatment of HeLa cells with GKI-1 reduces ENSA/ARPP19 phosphorylation levels, such that they are comparable to those obtained by siRNA depletion of GWL; resulting in a decrease in mitotic events, mitotic arrest/cell death and cytokinesis failure. Furthermore, GKI-1 will be a useful starting point for the development of more potent and selective GWL inhibitors. A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct.,Ocasio CA, Rajasekaran MB, Walker S, Le Grand D, Spencer J, Pearl FM, Ward SE, Savic V, Pearl LH, Hochegger H, Oliver AW Oncotarget. 2016 Aug 22. doi: 10.18632/oncotarget.11511. PMID:27563826[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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