THE AMP-ACTIVATED/SNF1 PROTEIN KINASE SUBFAMILY: Metabolic Sensors of the Eukaryotic Cell?

Abstract

Mammalian AMP-activated protein kinase and yeast SNF1 protein kinase are the central components of kinase cascades that are highly conserved between animals, fungi, and plants. The AMP-activated protein kinase cascade acts as a metabolic sensor or "fuel gauge" that monitors cellular AMP and ATP levels because it is activated by increases in the AMP:ATP ratio. Once activated, the enzyme switches off ATP-consuming anabolic pathways and switches on ATP-producing catabolic pathways, such as fatty acid oxidation. The SNF1 complex in yeast is activated in response to the stress of glucose deprivation. In this case the intracellular signal or signals have not been identified; however, SNF1 activation is associated with depletion of ATP and elevation of AMP. The SNF1 complex acts primarily by inducing expression of genes required for catabolic pathways that generate glucose, probably by triggering phosphorylation of transcription factors. SNF1-related protein kinases in higher plants are likely to be involved in the response of plant cells to environmental and/or nutritional stress.

A new serine/threonine protein kinase,Omphk1, essential to ventral body wall formation

“…1) was isolated in our efforts to identify new genes in mouse brain development by expression cloning (Murata et al, 2004) and is called Omphalocele kinase (Omphk1), because of its mutant phenotype as described below. The gene has a domain of 271 amino acids that is highly homologous to the serine/threonine kinase domain of the SNF1 subfamily (Hardie et al, 1998;Fig. 1C); it remains to be examined whether the gene product indeed has the kinase activity.…”

Nucleotide-gated KATPchannels integrated with creatine and adenylate kinases: Amplification, tuning and sensing of energetic signals in the compartmentalized cellular environment

“…Maintenance of homeostasis requires efficient transmission of energetic signals from sites of ATP generation to ATP sensors governing cellular response [1][2][3][4][5][6]. In the compartmentalized cell environment, energetic signaling must integrate detection, amplification and delivery of metabolic signals arising from deviations in adenine nucleotide levels [1][2][3][4][5][6][7][8][9].…”

“…In the compartmentalized cell environment, energetic signaling must integrate detection, amplification and delivery of metabolic signals arising from deviations in adenine nucleotide levels [1][2][3][4][5][6][7][8][9]. While the identity of energy-responsive elements is being increasingly resolved, the molecular mechanisms that synchronize metabolic sensor function with cell metabolism remain largely unknown.…”

“…At steady-state, with fluxes constant along x: (2) At steady-state nucleotide fluxes J ATP + J AMP + J ADP = 0 thus using Eq. 2: (4) At AK equilibrium in the submembrane compartment: [27,28,34], the diffusion coefficient D must be 1.5 10 -11 cm 2 /s to provide a 4 mM ΔATP, and thereby 3 mM [ATP] m necessary for merest K ATP channel activity (Fig. 3A).…”

Kinase activity-independent suppression of p73α by AMP-activated kinase α (AMPKα)

“…AMPK is a heterotrimeric serine/threonine kinase consisting of a catalytic a subunit (a1 or a2) and noncatalytic, regulatory b and g subunits, all of which are required for full kinase activity (Kemp et al, 2003). AMPK has been primarily described as a metabolic sensor that responds to intracellular ATP depletion induced by various metabolic stresses, and it is directly activated by increases in the AMP:ATP ratio (Hardie et al, 1998(Hardie et al, , 1999Kemp et al, 1999). Recent studies suggest that it can also be activated by upstream AMPK kinases such as the serine/threonine kinase LKB1, which phosphorylates the a subunit of AMPK at Thr 174 (at Thr 172 for a2) (Woods et al, 2003;Lizcano et al, 2004;Shaw et al, 2004), and possibly by Ca 2 þ /CaMdependent protein kinase kinase, which functions independently of AMP but phosphorylates the same residue in AMPK (Hawley et al, 2005;Hurley et al, 2005;Woods et al, 2005).…”