7, 8, 9ĪMPK is an evolutionarily conserved metabolic sensor that has a pivotal role in maintaining energy homeostasis by coordinating metabolic pathways to balance nutrient supply and demand.
#Pike alabama bead findings supplies full#
1 T172 phosphorylation in the activation loop of the α subunit is an absolute requirement for full activation of AMPK activity, 2, 3 and is mediated by at least two distinct upstream kinases, liver kinase B1 (LKB1) 4, 5, 6 and Ca 2+/calmodulin-dependent kinase kinase β (CaMKK β). An increase in intracellular AMP/ATP ratio results in allosteric activation of the kinase by protecting T172 from dephosphorylation. It is a heterotrimeric complex consisting of a catalytic α subunit and two regulatory ( β and γ) subunits. Thus, our findings provide additional layer of molecular regulation of the AMPK signaling pathway in cancer progression.ĪMP-activated protein kinase is activated under a variety of physiological and pathological stresses that increase the intracellular AMP/ATP ratio, either by increasing ATP consumption (exercise/muscle contraction) or by decreasing ATP production (e.g., glucose deprivation, hypoxia or ischemia). In human glioblastoma samples, PIKE-A expression inversely correlates with the p-AMPK levels, supporting that PIKE-A negatively regulates AMPK activity in cancers. Cell proliferation and oncogenic assays demonstrate that PIKE-A antagonizes tumor suppressive actions of AMPK. Mutation of Fyn phosphorylation sites on PIKE-A, depletion of Fyn, or pharmacological inhibition of Fyn blunts the association between PIKE-A and AMPK, resulting in loss of its inhibitory effect on AMPK.
PIKE-A directly interacts with AMPK catalytic alpha subunit and impairs T172 phosphorylation, leading to repression of its kinase activity on the downstream targets. Here, we show that PIKE-A binds to AMPK and blocks its tumor suppressive actions, which are mediated by tyrosine kinase Fyn. AMPK is mainly regulated by cellular AMP and phosphorylation by upstream kinases. The AMP-activated protein kinase, a key regulator of energy homeostasis, has a critical role in metabolic disorders and cancers.
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