Cancer-Associated Loss-of-Function Mutations Implicate DAPK3 as a Tumor-Suppressing Kinase

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 8; pp. 3152 - 3161
• Main Authors: BROGNARD, John, ZHANG, You-Wei, PUTO, Lorena A, HUNTER, Tony
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.04.2011
• Subjects: Amino Acid Sequence; Antineoplastic agents; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinases - genetics; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Cell Line, Tumor; Death-Associated Protein Kinases; HeLa Cells; Humans; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Medical sciences; Molecular Sequence Data; Mutation; Pharmacology. Drug treatments; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Loss function; Enzyme; Kinase; Transferases; Genetics; Mutation; Malignant tumor; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-3543

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.