10 Jak/Stat Signaling Pathway T(9;12)(p24;p13)TEL/JAK Akut LösemiHTLV-1JAK aktivasyonunda artışThe Jak/Stat Signaling PathwayA wide variety of extracellular signals activate the Stat (signal transducers and activators of transcription) class of transcription factors. Cytokines, lymphokines, and growth factors all signal through a related superfamily of cell surface receptors that are associated with and activate Janus kinases (Jaks). Ligand-induced dimerization of the receptor induces the reciprocal tyrosine phosphorylation of the associated Jaks, which, in turn, phosphorylates tyrosine residues on the cytoplasmic tail of the receptor. These phosphorylated tyrosines serve as docking sites for the Src Homology-2 (SH-2) domain of the Stat protein, and Jak catalyzes the tyrosine phosphorylation of the receptor-bound Stat. Phosphorylation of Stat at a conserved tyrosine residue induces SH-2-mediated homo- or heterodimerization, followed by translocation of the Stat dimer to the nucleus. Stat dimers bind to specific DNA response elements in the promoter region of target genes to activate gene expression. APS (adaptor molecule containing pleckstrin homology and SH-2 domains) can inhibit the Jak-Stat pathway by binding to the cytoplasmic domain of the receptor where it is phosphorylated (activated) by Jak. Activated APS binds to c-Cbl and blocks Stat activation.ReferencesWakioka, T., et al., APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl. Leukemia 13, (1999).Schindler, C., Cytokines and JAK-STAT signaling. Exp. Cell Res. 253, 7-14 (1999).
11 STAT-1: IFN’un antiproliferatif etkisi STAT-5: IL-3 ve GM-CSF’in proliferatif etkisiSTAT-3: IL-6 ve IL-10’a bağlı büyüme inhibisyonuSTAT inhibisyonu:SOCSPIAS
16 RAS SistemiRas proteini membrana bağlı reseptör tirozin kinaz aktivitesini sitoplazmik yolaklara ileten guanin nukleotid bağlama özelliği olan bir proteindir.Ras aracılı sinyali sitoplazmik alana ileten en iyi tanımlanmış protein raf’dır.Raf, ras’ı MAP kinazlara bağlayan bir serin / treonin kinazdır.Farklı ras proteinlerinin mutasyonları malignitede önemli rol oynarlar.
17 MAP Kinaz SistemiMAP kinaz, mitogen-activated protein kinase demektir.Aynı zamanda extracellular signal regulating kinases (ERK) olarak da bilinir.MAP kinaz dual fosforilasyon ile aktive olur ve PP2a ya da CD45 tarafından inaktive edilir.Bu aile membran reseptör tirozin kinazları aktive eden mitojenik sinyalin nukleusa ulaşımında önemli rol oynamaktadır.
18 MAP kinase ileti sistemi MAP-kinase-kinase-kinaseMAP kinase ileti sistemiMAP-kinase-kinaseMAP-kinasechanges in protein activitychanges in gene expression
37 Nuclear Factor kappa B ( NF-κB ) 2 domains: one binds DNA; the other activates transcription by interacting with other components of the transcriptional machinery.Have specific motifs in their DNA binding domains e.g. zinc fingers, leucine zippers, helix-loop-helix and helix-turn-helix
38 NF-κB Involved in various aspects of the immune response Target of Protein Kinase C signalling as well as other pathwaysActivity is regulated by translocation from cytoplasm to nucleusIn inactive form, NF-kB is complexed to its inhibitory subunit I kappa B (IkB) in the cytoplasmActivation of various pathways leads to phosphorylation of IkB, which targets it for proteolytic degradation.Destruction of the inhibitory subunit allows NF-kB free to move to the nucleus where it activates genes.
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