AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade
Program in Molecular Medicine
A Kinase Anchor Proteins; Amino Acid Sequence; Animals; Cell Line; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Humans; *MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Molecular Sequence Data; Protein Kinases; Proto-Oncogene Proteins; Sequence Alignment
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
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.
DOI of Published Version
Nat Cell Biol. 2010 Dec;12(12):1242-9. doi: 10.1038/ncb2130. Epub 2010 Nov 21. Link to article on publisher's site
Nature cell biology
Smith, F. Donelson; Langeberg, Lorene K.; Cellurale, Cristina Arrigo; Pawson, Tony; Morrison, Deborah K.; Davis, Roger J.; and Scott, John D., "AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade" (2010). Davis Lab Publications. 29.