title: AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade.
abstract: Mitogen-activated protein kinase (MAPK) cascades propagate a variety of cellular activities. Processive relay of signals through RAF-MEK-ERK modulates cell growth and proliferation. Signalling through this ERK cascade is frequently amplified in cancers, and drugs such as sorafenib (which is prescribed to treat renal and hepatic carcinomas) and PLX4720 (which targets melanomas) inhibit RAF kinases. Natural factors that influence ERK1/2 signalling include the second messenger cyclic AMP. However, the mechanisms underlying this cascade have been difficult to elucidate. We demonstrate that the A-kinase-anchoring protein AKAP-Lbc and the scaffolding protein kinase suppressor of Ras (KSR-1) form the core of a signalling network that efficiently relay signals from RAF, through MEK, and on to ERK1/2. AKAP-Lbc functions as an enhancer of ERK signalling by securing RAF in the vicinity of MEK1 and synchronizing protein kinase A (PKA)-mediated phosphorylation of Ser 838 on KSR-1. This offers mechanistic insight into cAMP-responsive control of ERK signalling events.
authors.affiliation: Howard Hughes Medical Institute, Department of Pharmacology, University of Washington School of Medicine, 1959 Pacific Avenue NE, Seattle, WA 98195, USA.
authors.forename: F Donelson
authors.initials: FD
authors.lastname: Smith
authors.forename: Lorene K
authors.initials: LK
authors.lastname: Langeberg
authors.forename: Cristina
authors.initials: C
authors.lastname: Cellurale
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Morrison
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D015778:Minor Histocompatibility Antigens; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008969:Molecular Sequence Data; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; D015778:Minor Histocompatibility Antigens; D011518:Proto-Oncogene Proteins; D000242:Cyclic AMP; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3