four.one.cAMregulatoof the MEK ERK pathway The molecular mechansm for your phenotypc dfference the cAMmtogenc response betweenormal and PKD cells s lnked towards the dfferental regulatoof the Raf MEK ERK sgnalng pathway.B Raf, Raf one in addition to a Raf really are a famy of serne threonne knases which might be central ntermedates transmttng extracellular sgnals, ncludng people from growth things andhormones, for the MEK ERK pathway.ERK actvatos mportant for cell prolferatodurng improvement and coordnates cell cycle re entry durng tssue repar.Ras, modest GTbndng protens, recrut Raf for the plasma membrane whch s essental for Raf actvaton.addton, Raf knases are regulated by multple pathways by way of phosphorylatoof specfc serne and threonne resdues.The balance betweethe phosphorylatoof stmulatory and nhbtory stes s a significant element Raf regulatoof ERK medated cell prolferaton.Actvated Raf phosphorylates and stmulates MEK1 two, whch turn, phosphorylates and actvates ERK1 2.
There s translocatoof actvated ERK nto the nucleus the place t upregulates the transcrptonal actvty of a variety of genes nvolved cell prolferaton.The Raf MEK ERK pathway exerts ts effects ocell prolferatothrough nductoof cell cycle regulatory protens, ncludng the cycldependent knases, cyclns and p21, and transcrptofactors which include c myc and A1.The capacty for cAMto stmulate or nhbt ERK accounts for a lot of within the cell style specfc cAMeffects order CX-4945 ocell prolferaton.astrocytes, smooth muscle cells, fbroblasts and mesangal cells, cAMnhbts ERK actvty and cell prolferaton.Othe otherhand, cAMstmulates ERK and prolferatoof other cell sorts, ncludng thyrod cells,hepatocytes and Pc twelve neuronal cells.Regulatoof cAMsgnalng to ERK happens in the degree of Raf.Whe B Raf and Raf one sharehomology amno acd sequence,the 2 knases are dfferentally regulated by cAMP.Two actvatostes specific Src inhibitor Raf one are conserved B Raf, and also the phosphorylatoof these resdues s mportant for knase actvty.nonetheless, unlke B Raf, S338 and341 of Raf one will need to also be phosphorylated for knase actvaton.
The correspondng serne resdue B Raf s consttutvely phosphorylated and also the tyrosne resdue

at 341 of Raf 1 s replaced B Raf wth aaspartc acd, whch mmcs phosphorylated tyrosne.Consequently, fewer phosphorylatoevents are vital to actvate B Raf compared to Raf one.A further mportant dfference s that Raf 1has 3 PKA nhbtory phosphorylatostes, any 1 of whch cablock Ras bndng to Raf 1 and protect against Raf one translocatoto the membrane.These PKA phosphorylatostes are not conserved B Raf makng B Raf resstant to nhbtoby cAMP,nstead, PKA phosphorylatostmulates B Raf actvty.addton, B Rafhas a better affnty for MEK and produces a stronger MEK stmulatothaRaf 1.Therefore, B Rafhashgher basal actvty in contrast to Raf one and seems to be posed for actvatoby cAMP.