title: LKB1 is the upstream kinase in the AMP-activated protein kinase cascade.
abstract: Inactivating mutations in the protein kinase LKB1 lead to a dominantly inherited cancer in humans termed Peutz-Jeghers syndrome. The role of LKB1 is unclear, and only one target for LKB1 has been identified in vivo [3]. AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that plays a pivotal role in energy homeostasis. AMPK may have a role in protecting the body from metabolic diseases including type 2 diabetes, obesity, and cardiac hypertrophy. We previously reported the identification of three protein kinases (Elm1, Pak1, and Tos3 [9]) that lie upstream of Snf1, the yeast homologue of AMPK. LKB1 shares sequence similarity with Elm1, Pak1, and Tos3, and we demonstrated that LKB1 phosphorylates AMPK on the activation loop threonine (Thr172) within the catalytic subunit and activates AMPK in vitro [9]. Here, we have investigated whether LKB1 corresponds to the major AMPKK activity present in cell extracts. AMPKK purified from rat liver corresponds to LKB1, and blocking LKB1 activity in cells abolishes AMPK activation in response to different stimuli. These results identify a link between two protein kinases, previously thought to lie in unrelated, distinct pathways, that are associated with human diseases.
authors: Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
authors: Angela
authors: A
authors: Woods
authors: Stephen R
authors: SR
authors: Johnstone
authors: Kristina
authors: K
authors: Dickerson
authors: Fiona C
authors: FC
authors: Leiper
authors: Lee G D
authors: LG
authors: Fryer
authors: Dietbert
authors: D
authors: Neumann
authors: Uwe
authors: U
authors: Schlattner
authors: Theo
authors: T
authors: Wallimann
authors: Marian
authors: M
authors: Carlson
authors: David
authors: D
authors: Carling
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D015153:Blotting, Western; D002852:Chromatography, Ion Exchange; D004789:Enzyme Activation; D008099:Liver / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats
chemical_list: D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases