| Cellular signaling pathways form a huge network within cells.It maintains the survival and metabolism of cells,and controls the process of “from birth to death”.So to understand cell signal transduction mechanisms can help people to explore the mysteries of life.Many aspects are incorporated in cell signals.Both magnitude and duration are a part of cell signaling and important in determining its cellular functions.Insulin signaling pathway is an important part of cellular signaling network and its feedback mechanism is quite complex.Insulin-induced degradation of insulin receptor substrate 1(IRS1)represents a key negative feedback loop which restrains insulin signaling.However,molecular mechanisms regulating stability of IRS1 in response to cellular stress are not well understood.Fatty acids,as one of the important elements that constitute life,compose a huge membrane structure of cells,providing walls for the functioning of various organelles,but their role in signal transduction has not been completely revealed.CD36 binds to a variety of lipid ligands and its contribution to insulin resistance has been extensively studied,but the exact regulation of insulin sensitivity by CD36 is highly controversial.We showed that CD36 knockdown in C2C12 myotubes accelerates the activation of insulin signaling,but the activated signaling sustains for much shorter period of time,leading to exacerbated insulin-induced insulin resistance.This is likely due to enhanced insulin-induced IRS1 degradation in CD36 knockdown myotubes.CD36 functions through ubiquitination-dependent binding to IRS1 and inhibits IRS1 interaction with CUL7,to decrease the ubiquitinational levels and delay degradation of IRS1.However,pretreatment with fatty acids can prevent the function of CD36 in this area.Moreover,Insulin signaling plays an important role in cancer metabolism,including proliferation,migration,invasion and drug resistance.The fatty acids are transferred into the cell by CD36 and other fatty acid binding proteins,some of them are involved in the synthesis of complex lipids,and the others are given new functions by various modifications.Many fatty acid modifications and related enzymes are involved in the regulation of insulin signaling pathways.Our results indicated that fatty acid 2-hydroxylase(FA2H)can regulate the expression of insulin receptor(IR)by a positive feedback of insulin signaling through ERK1/2 activation,and control the proliferation of MCF7.Treatment with ERK1/2 inhibitor,U0126,can decrease the both protein and RNA expression of IR,and inhibit the cell prolitferation.Collectively,our works indicated the regulation of insulin signaling by fatty acid sensing and modification,which may provide a potential strategy for ameliorating insulin sensitivity or preventing and treating type 2 diabetes mellitus and cancer. |
