title: Cancer-associated loss-of-function mutations implicate DAPK3 as a tumor-suppressing kinase.
abstract: Cancer kinome sequencing studies have identified several protein kinases predicted to possess driver (i.e., causal) mutations. Using bioinformatic applications, we have pinpointed DAPK3 (ZIPK) as a novel cancer-associated kinase with functional mutations. Evaluation of nonsynonymous point mutations, discovered in DAPK3 in various tumors (T112M, D161N, and P216S), reveals that all three mutations decrease or abolish kinase activity. Furthermore, phenotypic assays indicate that the three mutations observed in cancer abrogate the function of the kinase to regulate both the cell cycle and cell survival. Coexpression of wild-type (WT) and cancer mutant kinases shows that the cancer mutants dominantly inhibit the function of the WT kinase. Reconstitution of a non-small cell lung cancer cell line that harbors an endogenous mutation in DAPK3 (P216S) with WT DAPK3 resulted in decreased cellular aggregation and increased sensitivity to chemotherapy. Our results suggest that DAPK3 is a tumor suppressor in which loss-of-function mutations promote increased cell survival, proliferation, cellular aggregation, and increased resistance to chemotherapy.
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK, Paterson Institute for Cancer Research, The University of Manchester, Manchester, United Kingdom. jbrognard@picr.man.ac.uk
authors.forename: John
authors.initials: J
authors.lastname: Brognard
authors.forename: You-Wei
authors.initials: YW
authors.lastname: Zhang
authors.forename: Lorena A
authors.initials: LA
authors.lastname: Puto
authors.forename: Tony
authors.initials: T
authors.lastname: Hunter
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D025521:Tumor Suppressor Proteins; C579101:DAPK3 protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases