title: A novel LKB1 isoform enhances AMPK metabolic activity and displays oncogenic properties.
abstract: The LKB1 tumor suppressor gene encodes a master kinase that coordinates the regulation of energetic metabolism and cell polarity. We now report the identification of a novel isoform of LKB1 (named ΔN-LKB1) that is generated through alternative transcription and internal initiation of translation of the LKB1 mRNA. The ΔN-LKB1 protein lacks the N-terminal region and a portion of the kinase domain. Although ΔN-LKB1 is catalytically inactive, it potentiates the stimulating effect of LKB1 on the AMP-activated protein kinase (AMPK) metabolic sensor through a direct interaction with the regulatory autoinhibitory domain of AMPK. In contrast, ΔN-LKB1 negatively interferes with the LKB1 polarizing activity. Finally, combining in vitro and in vivo approaches, we showed that ΔN-LKB1 has an intrinsic oncogenic property. ΔN-LKB1 is expressed solely in the lung cancer cell line, NCI-H460. Silencing of ΔN-LKB1 decreased the survival of NCI-H460 cells and inhibited their tumorigenicity when engrafted in nude mice. In conclusion, we have identified a novel LKB1 isoform that enhances the LKB1-controlled AMPK metabolic activity but inhibits LKB1-induced polarizing activity. Both the LKB1 tumor suppressor gene and the oncogene ΔN-LKB1 are expressed from the same locus and this may account for some of the paradoxical effects of LKB1 during tumorigenesis.
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France [4] Equipe labellisée LNCC, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Dahmani
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France [4] Equipe labellisée LNCC, Paris, France.
authors.forename: P-A
authors.initials: PA
authors.lastname: Just
authors.affiliation: Institut Albert Bonniot, CRI Inserm/UJF U823, Rond Point de la Chantourne, La Tronche, France.
authors.forename: A
authors.initials: A
authors.lastname: Delay
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France [4] Equipe labellisée LNCC, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Canal
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France [4] Equipe labellisée LNCC, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Finzi
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Prip-Buus
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Lambert
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Sujobert
authors.affiliation: Institut Albert Bonniot, CRI Inserm/UJF U823, Rond Point de la Chantourne, La Tronche, France.
authors.forename: K
authors.initials: K
authors.lastname: Buchet-Poyau
authors.affiliation: Section of Cardiology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Miller
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France [4] Equipe labellisée LNCC, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Cavard
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France [4] Equipe labellisée LNCC, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Marmier
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France [4] Equipe labellisée LNCC, Paris, France [5] Pathology Unit, Hôpital Cochin, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Terris
authors.affiliation: Institut Albert Bonniot, CRI Inserm/UJF U823, Rond Point de la Chantourne, La Tronche, France.
authors.forename: M
authors.initials: M
authors.lastname: Billaud
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] Cnrs, UMR8104, Paris, France [3] Université Paris Descartes, Paris, France [4] Equipe labellisée LNCC, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Perret
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017398:Alternative Splicing; D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases