Alteration of beta-secretase traffic by the receptor tyrosine kinase signaling pathway - a new mechanism for regulating Alzheimer's beta-amyloid production

摘要

The receptor tyrosine kinases (RTKs) are a family of cellsurface proteins with diverse functions in proliferation, differentiation or cell-cell communication. When a specific ligand binds to its cognate receptor, a conformational change of this receptor due to the ligand-receptor interaction willlead to activation of the intrinsic tyrosine kinase residing inthe intracellular domain of the receptor. The activation ofthis tyrosine kinase is essential for transducing the signals toa cascade of its downstream molecules that eventually causerelated physiological responses [1]. For example, binding ofnerve growth factor (NGF) to its receptor TrkA is essentialfor the proper development, patterning, and maintenanceof the mammalian nervous system. This ligand and receptor interaction will lead to the formation of a crab-shaped homodimeric TrkA structure [2], and the subsequent activation of its intrinsic RTK will cause auto-phosphorylationof its own intracellular tyrosine residues. PhosphorylatedTrkA receptors recruit and increase the phosphorylationof PLC-gamma and She, which leads to activation of either thePI3K/Akt pathway or Ras/raf/ERK pathway. In the brainof Alzheimer's disease (AD) patients, alterations of nervegrowth factor (NGF) and its receptor TrkA have beenreported to associate with AD pathogenesis [3]. However,the underlying mechanisms remain elusive.