JNK and ERK8 as downstream effectors of receptor tyrosine kinases
Iavarone, Carlo (2006) JNK and ERK8 as downstream effectors of receptor tyrosine kinases. [Tesi di dottorato] (Inedito)
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MAP kinases are a super-family of serine-threonine protein kinases expressed in all eukaryotic cells. In mammals, there are many MAP kinases with different biological functions, grouped in distinctly regulated groups, ERK1/2 (extracellular signal related kinase, ERK), JNKs (jun amino terminal kinase, JNK), p38 and “atypical” MAP kinases. The MAP kinase transduction system is particularly important in growth factors signaling, which in turn control cell growth, proliferation, differentiation, survival and migration by activating receptor tyrosine kinase (RTK) family members, as platelet-derived growth factor (PDGF) and RET. In the first report, we show that JNK is required for PDGF induction of c-myc expression. Furthermore, we identify a phylogenetically conserved AP-1 responsive element in the human, mouse and even drosophila c-myc promoter. Such element binds, in vivo, to members of the Jun family of transcription factors, c-Jun and JunD, as indicated by chromatin immunoprecipitation analysis. Finally, we show that, through this element, PDGF is able to control the activity of the c-myc transcription factor promoter in an AP-1 dependent fashion, implying the existence of a novel signaling pathway linking the PDGF receptor, through JNK and Jun proteins, to nuclear events culminating in the expression of the c-myc proto-oncogene. In the second report, we show that RET/PTC3 activates Erk8, a new member of “atypical” MAP kinases group, by an Abl-dependent but Src-independent mechanism and demonstrate a key role for Tyr981 of RET/PTC3 in the initiation of such signaling pathway. Also, by using an alternative Erk8 splice variant, Erk8, lacking the C-terminal domain, we establish a role for this region in the activation of this MAP kinase by RET/PTC3. Finally, the use of a dominant interfering molecule for Erk8 revealed that RET/PTC3 requires this MAP kinase to stimulate the c-jun transcription factor promoter.
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