協同活化 JAK1 和 JAK2 於造血幹原母細胞中功能角色的探討

1. 協同活化JAK1和JAK2於造血幹原母細胞中功能角色的探討協同活化JAK1和JAK2於造血幹原母細胞中功能角色的探討 • 血球生成的過程中受到很多種細胞間素的調控。其中Janus kinase (JAK)蛋白質在細胞間素調控血球生成扮演著重要的角色。許多的細胞間素可以活化兩個或兩個以上的JAKs。這些同時活化的JAKs如何影響細胞活性的作用機轉卻不清楚。先前在我們實驗室中發現,同時活化JAK1和JAK2會促進tyrosine phosphorylation 的訊息傳遞,並且會進一步的活化Signal Transduction and Activators of Transcription 5 ( STAT5)，Akt 和Mitogen-Activated Protein Kinase (MAPK)。在這個實驗，為了更進一步證明JAK1和JAK2的協同活化作用，將其中的一個JAK發生KE突變，利用已建立好的細胞株〝Ba/F3-JAK1KE+2〞細胞和〝Ba/F3-JAK1+2KE細胞〞觀察是否對細胞訊號傳遞過程及細胞活性發生影響。實驗結果發現這些細胞株的tyrosine phosphorylation 的訊息傳遞以及 STAT5，Akt 和MAPK的磷酸化遠比同時活化JAK1和JAK2來的低，並且無法維持細胞增殖的能力。更進一步的，協同活化的JAK1和JAK2可能透過與受體的結合，形成複合體來傳遞訊息。這些結果顯示JAK1和JAK2協同活化訊息傳遞的作用以及提供細胞增殖的活性，需要正常激素活性，當其中一個JAK的活性突變，則無此作用。

2. Synergistic Activation of JAK1 and JAK2 and Functional Characterization in Hematopoietic Progenitor Cells • Cytokines are able to induce various signaling pathways during hematopoiesis. Janus kinases (JAKs) were found to play a very important role in some signaling pathways. In most cases, more than one JAK will be simultaneously activated by specific cytokine. However, it is not clear that how simultaneous activated-JAKs can affect cellular activity. Our previous results have shown that phosphorylation signaling, including tyrosine phosphorylation of STAT5, MAPK and Akt, can be detected in hematopoietic progenitor cells co-transfected with JAK1 and JAK2. In present study, one of JAKs was replaced by JAK1 or JAK2 inactive mutants (KE). The resulted two cell lines, Ba/F3-JAK1KE+2 and Ba/F3-JAK1+2KE, respectively, indeed produce either inhibited or reduced phosphorylation profiles of STAT5, MAPK and Akt, as well as proliferation activity of cells. Furthermore, it is indicated that synergistic activated—JAK1 and —JAK2 may associate with receptors and form complexes to pass signals to downstream components of pathway. These results show that both JAK1 and JAK2 need to be activated to produce synergistic effect for signal transduction and cellular proliferation.