title: praja2 regulates KSR1 stability and mitogenic signaling.
abstract: The kinase suppressor of Ras 1 (KSR1) has a fundamental role in mitogenic signaling by scaffolding components of the Ras/MAP kinase pathway. In response to Ras activation, KSR1 assembles a tripartite kinase complex that optimally transfers signals generated at the cell membrane to activate ERK. We describe a novel mechanism of ERK attenuation based on ubiquitin-dependent proteolysis of KSR1. Stimulation of membrane receptors by hormones or growth factors induced KSR1 polyubiquitination, which paralleled a decline of ERK1/2 signaling. We identified praja2 as the E3 ligase that ubiquitylates KSR1. We showed that praja2-dependent regulation of KSR1 is involved in the growth of cancer cells and in the maintenance of undifferentiated pluripotent state in mouse embryonic stem cells. The dynamic interplay between the ubiquitin system and the kinase scaffold of the Ras pathway shapes the activation profile of the mitogenic cascade. By controlling KSR1 levels, praja2 directly affects compartmentalized ERK activities, impacting on physiological events required for cell proliferation and maintenance of embryonic stem cell pluripotency.
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, IEOS-CNR, CEINGE University Federico II, Naples 80131, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Rinaldi
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, IEOS-CNR, CEINGE University Federico II, Naples 80131, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Delle Donne
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, IEOS-CNR, CEINGE University Federico II, Naples 80131, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Sepe
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, IEOS-CNR, CEINGE University Federico II, Naples 80131, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Porpora
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, IEOS-CNR, CEINGE University Federico II, Naples 80131, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Garbi
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, IEOS-CNR, CEINGE University Federico II, Naples 80131, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Chiuso
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, IEOS-CNR, CEINGE University Federico II, Naples 80131, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gallo
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, IEOS-CNR, CEINGE University Federico II, Naples 80131, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Parisi
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, IEOS-CNR, CEINGE University Federico II, Naples 80131, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Russo
authors.affiliation: Institute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.|Bioinformatics Institute (BII), Agency for Science Technology and Research (A*STAR), Singapore 138671, Singapore.
authors.forename: V
authors.initials: V
authors.lastname: Bachmann
authors.affiliation: Institute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.|Bioinformatics Institute (BII), Agency for Science Technology and Research (A*STAR), Singapore 138671, Singapore.
authors.forename: R G
authors.initials: RG
authors.lastname: Huber
authors.affiliation: Institute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.|Bioinformatics Institute (BII), Agency for Science Technology and Research (A*STAR), Singapore 138671, Singapore.
authors.forename: E
authors.initials: E
authors.lastname: Stefan
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, IEOS-CNR, CEINGE University Federico II, Naples 80131, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Russo
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, IEOS-CNR, CEINGE University Federico II, Naples 80131, Italy.
authors.forename: A
authors.identifier: 0000-0002-7932-2170
authors.initials: A
authors.lastname: Feliciello
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005576:Colforsin / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics* / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology; D008958:Models, Molecular; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D016415:Sequence Alignment; D015398:Signal Transduction; D040681:Structural Homology, Protein; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D008934:Mitogens; D016222:Fibroblast Growth Factor 2; D005576:Colforsin; D004815:Epidermal Growth Factor; C577689:PJA2 protein, human; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C097199:KSR-1 protein kinase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3