The result of cAMoB Raf sgnalng to MEK s cell kind and or articles dependent.You’ll find two major soforms of B Raf produced by alternatve splcng.Vossler.had advised that cAMstmulates ERK cells that express the 95 kD soform of B Raf and nhbts ERK cells lackng ths soform.yet, other reviews, cAMwas showto nhbt B Raf cells expressng kinase inhibitor SP600125 both soforms, ndcatng that B Raf regulatoby cAMmay be dependent ocellular condtons.partcular, B Rafhas beeshowto be negatvely regulated by Akt, a serne threonne knase, by means of a Ca2 dependent and phosphonostde 3 knase dependent manner.Akt phosphorylates B Raf at S365 and T440, mportant stes for B Raf nhbton, and mutatons of resdues close to T440 stop phosphorylatoby Akt, leadng to a reduction of Akt medated B Raf nhbton.These mutatons are assocated wth actvated ERK and ncreased cell prolferatocertacancers, ncludng lung tiny cell carcnoma and malgnant melanoma.four.two.
Ca2 regulatoof kinase inhibitor Temsirolimus cAMdependent ERK actvatoand cell prolferatoEvdence ndcatng that PC1, PC2 and fbrocystnormally contrbute to the regulatoof ntracellular Ca2 led to thehypothess that a reductontracellular Ca2 cystc cells may possibly be the bass for cAMdependent cell prolferaton.To test the purpose of Ca2, NHK cells and mmortalzed mouse collectng duct M one cells were handled wth Ca2 channel blockers or EGTA, a Ca2 chelator, to reduced ntracellular Ca2 levels.these experments, Ca2 restrctoconverted the usual cAMgrowth nhbted phenotype to a cAMgrowth stmulated phenotype, mmckng PKD cells.these Ca2 restrcted cells, cAMstmulated B Raf knase actvty and ncreased phoshorylated ERK and cell prolferaton.Ca2 restrctodecreased the degree of phosphorylated Akt, whch generally represses B Raf.Drect pharmacologcal nhbtoof Akt also brought on cAMdependent actvatoERK and cell prolferaton.Also, secure overexpressothe C termnal ta of PC1 M one cells, whch s considered to act a domnant negatve manner, decreased ntracellular Ca2, and swtched the cAMresponse, such that cAMactvated B Raf, ERK and cell prolferaton.
nterestngly, the Ca2 swtch requred severalhours, suggestng that addtonal Ca2 dependent mechansms are nvolved.a recprocal study, remedy ofhumaADPKD and ARPKD cells wth Bay K8644, a Ca2 channel actvator, or A23187, a Ca2 onophore, induced a sustaned ncrease regular state Ca2 amounts and thoroughly reversed the mtogenc response to cAMP,therefore, rescung the typical ant mtogenc response to cAMP.Untreated ADPKD cellshad reduced basal Akt actvty compared to NHK cells and rasng ntracellular

Ca2 ncreased Akt actvty and suppressed B Raf, thereby blockng cAMdependent ERK actvatoand cell prolferaton.Taketogether, these studes help thehypothess that a reductontracellular Ca2, secondary to mutatons the PKD genes, decreases Akt actvty, relevng Akt nhbtoof B Raf, and allowng cAMactvatoof the B Raf MEK ERK sgnalng and cell prolferaton.