title: A cancer-associated mutation in atypical protein kinase Cι occurs in a substrate-specific recruitment motif.
abstract: Atypical protein kinase Cι (PKCι) has roles in cell growth, cellular polarity, and migration, and its abundance is frequently increased in cancer. We identified a protein interaction surface containing a dibasic motif (RIPR) that bound a distinct subset of PKCι substrates including lethal giant larvae 2 (LLGL2) and myosin X, but not other substrates such as Par3. Further characterization demonstrated that Arg471 in this motif was important for binding to LLGL2, whereas Arg474 was critical for interaction with myosin X, indicating that multiple complexes could be formed through this motif. A somatic mutation of the dibasic motif (R471C) was the most frequent mutation of PKCι in human cancer, and the intact dibasic motif was required for normal polarized epithelial morphogenesis in three-dimensional cysts. Thus, the R471C substitution is a change-of-function mutation acting at this substrate-specific recruitment site to selectively disrupt the polarizing activity of PKCι.
authors.affiliation: 1Protein Phosphorylation Laboratory, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Linch
authors.forename: Marta
authors.initials: M
authors.lastname: Sanz-Garcia
authors.forename: Erika
authors.initials: E
authors.lastname: Soriano
authors.forename: Yixiao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Philippe
authors.initials: P
authors.lastname: Riou
authors.forename: Carine
authors.initials: C
authors.lastname: Rosse
authors.forename: Angus
authors.initials: A
authors.lastname: Cameron
authors.forename: Phillip
authors.initials: P
authors.lastname: Knowles
authors.forename: Andrew
authors.initials: A
authors.lastname: Purkiss
authors.forename: Svend
authors.initials: S
authors.lastname: Kjaer
authors.forename: Neil Q
authors.initials: NQ
authors.lastname: McDonald
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Parker
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000599:Amino Acids, Diamino / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D016764:Cell Polarity / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000737:chemistry* / Q000235:genetics*; D061985:Madin Darby Canine Kidney Cells; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D010766:Phosphorylation; D011487:Protein Conformation; D011493:Protein Kinase C / Q000737:chemistry* / Q000235:genetics*; D016415:Sequence Alignment; D013379:Substrate Specificity; D000099293:Protein Kinase C-lambda
chemical_list: D000599:Amino Acids, Diamino; D003598:Cytoskeletal Proteins; D007527:Isoenzymes; D009363:Neoplasm Proteins; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda; C526122:llgl2 protein, human