AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade

被引：105

作者：

Smith, F. Donelson ^{[1
]}

Langeberg, Lorene K. ^{[1
]}

Cellurale, Cristina ^{[2
]}

Pawson, Tony ^{[3
]}

Morrison, Deborah K. ^{[4
]}

Davis, Roger J. ^{[2
]}

Scott, John D. ^{[1
]}

机构：

[1] Univ Washington, Sch Med, Dept Pharmacol, Howard Hughes Med Inst, Seattle, WA 98195 USA

[2] Univ Massachusetts, Howard Hughes Med Inst, Program Mol Med, Worcester, MA 01605 USA

[3] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada

[4] NCI, Lab Cell & Dev Signalling, Frederick, MD 21702 USA

来源：

NATURE CELL BIOLOGY | 2010年 / 12卷 / 12期

关键词：

PROTEIN-KINASE-A; SIGNALING PATHWAYS; IN-VIVO; B-RAF; ACTIVATION; CAMP; SCAFFOLD; INHIBITION; KSR;

D O I：

10.1038/ncb2130

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Mitogen-activated protein kinase (MAPK) cascades propagate a variety of cellular activities(1). Processive relay of signals through RAF-MEK-ERK modulates cell growth and proliferation(2,3). 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(4,5). Natural factors that influence ERK1/2 signalling include the second messenger cyclic AMP(6,7). 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.

引用

页码：1242 / U287

页数：16

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