Rabbit Anti-DUSP6 monoclonal antibody, clone TS40-10

Serine-arginine protein kinase 1 (SRPK1) phosphorylates proteins involved in the regulation of several mRNA processing pathways including alternative splicing. SRPK1 has been reported to be over-expressed in multiple cancers including prostate, breast, lung and glioma. Several studies further identified that inhibition of SRPK1 showed tumor-suppressive effects, thus raising SRPK1 as a novel candidate chemotherapy target. Interestingly, SRPK1 plays tumor suppressing role in mouse embryonic fibroblasts, on that SRPK1-silencing induces cell transformation. Therefore, the effect of SRPK1 seems heterogeneously in different cell types and tissues. The existence and role of SRPK1 in gastric cancer (GC) hasn't been reported. Here we investigated the expression pattern of SRPK1 in GC by immunohistochemistry and found that it was up-regulated in tumor tissues, where its expression was correlated with tumor grade and prognosis. Further, we explored the signaling mechanism of SRPK1 in promoting GC progression, which revealed that both PP2A and DUSP6 phosphatases impaired the oncogenic effects of SRPK1. However, we didn't find any direct interaction between SRPK1 with PP2A or DUSP6, indicating PP2A and DUSP6 function by regulating the downstream effectors of SRPK1. Our study not only revealed the clinical significance of SRPK1 in GC, but also provided new evidence for its signaling modulation which is invaluable for novel chemotherapy development.

The same pathway, such as the mitogen-activated protein kinase (MAPK) pathway, can produce different cellular responses, depending on stimulus or cell type. We examined the phosphorylation dynamics of the MAPK kinase MEK and its targets extracellular signal-regulated kinase 1 and 2 (ERK1/2) in primary hepatocytes and the transformed keratinocyte cell line HaCaT A5 exposed to either hepatocyte growth factor or interleukin-6. By combining quantitative mass spectrometry with dynamic modeling, we elucidated network structures for the reversible threonine and tyrosine phosphorylation of ERK in both cell types. In addition to differences in the phosphorylation and dephosphorylation reactions, the HaCaT network model required two feedback mechanisms, which, as the experimental data suggested, involved the induction of the dual-specificity phosphatase DUSP6 and the scaffold paxillin. We assayed and modeled the accumulation of the double-phosphorylated and active form of ERK1/2, as well as the dynamics of the changes in the monophosphorylated forms of ERK1/2. Modeling the differences in the dynamics of the changes in the distributions of the phosphorylated forms of ERK1/2 suggested that different amounts of MEK activity triggered context-specific responses, with primary hepatocytes favoring the formation of double-phosphorylated ERK1/2 and HaCaT A5 cells that produce both the threonine-phosphorylated and the double-phosphorylated form. These differences in phosphorylation distributions explained the threshold, sensitivity, and saturation of the ERK response. We extended the findings of differential ERK phosphorylation profiles to five additional cultured cell systems and matched liver tumor and normal tissue, which revealed context-specific patterns of the various forms of phosphorylated ERK.