title: The protein kinase Akt/PKB regulates both prelamin A degradation and Lmna gene expression.
abstract: The serine/threonine kinase Akt/PKB is a major signaling hub integrating metabolic, survival, growth, and cell cycle regulatory signals. The definition of the phospho-motif cipher driving phosphorylation by Akt led to the identification of hundreds of putative substrates, and it is therefore pivotal to identify those whose phosphorylation by Akt is of consequence to biological processes. The Lmna gene products lamin A/C and the lamin A precursor prelamin A are type V intermediate filament proteins forming a filamentous meshwork, the lamina, underneath the inner nuclear membrane, for nuclear envelope structures organization and interphase chromatin anchoring. In our previous work, we reported that A-type lamins are phosphorylated by Akt at S301 and S404 in physiological conditions and are therefore bona fide substrates of Akt. We report here that Akt phosphorylation at S404 targets the precursor prelamin A for degradation. We further demonstrate that Akt also regulates Lmna transcription. Our study unveils a previously unknown function of Akt in the control of prelamin A stability and expression. Moreover, given the large number of diseases related to prelamin A, our findings represent a further important step bridging basic A-type lamin physiology to therapeutic approaches for lamin A-linked disorders.
authors: Cellular Signaling Laboratory, Department of Surgery, Medicine, Dentistry, and Morphology, University of Modena and Reggio Emilia, Modena, Italy.
authors: Jessika
authors: J
authors: Bertacchini
authors: Francesca
authors: F
authors: Beretti
authors: Vittoria
authors: V
authors: Cenni
authors: Marianna
authors: M
authors: Guida
authors: Federica
authors: F
authors: Gibellini
authors: Laura
authors: L
authors: Mediani
authors: Oriano
authors: O
authors: Marin
authors: Nadir M
authors: NM
authors: Maraldi
authors: Anto
authors: A
authors: de Pol
authors: Giovanna
authors: G
authors: Lattanzi
authors: Lucio
authors: L
authors: Cocco
authors: Sandra
authors: S
authors: Marmiroli
mesh_terms: D000818:Animals; D002460:Cell Line; D059565:G2 Phase Cell Cycle Checkpoints; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007399:Interphase; D034904:Lamin Type A / Q000235:genetics*; D051379:Mice; D008938:Mitosis; D008954:Models, Biological; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism*; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; C576142:Lmna protein, mouse; D009687:Nuclear Proteins; D011498:Protein Precursors; D034741:RNA, Small Interfering; C090764:prelamin A; D051057:Proto-Oncogene Proteins c-akt
keywords: 14.3.3; cell cycle; lamina phosphorylation; nuclear signaling; nucleus