35 research outputs found
Predicting the response to sorafenib in hepatocellular carcinoma: where is the evidence for phosphorylated extracellular signaling-regulated kinase (pERK)?
The approval of sorafenib and active development of many other molecularly targeted agents in hepatocellular carcinoma (HCC) have presented a challenge to understand the mechanism of action of sorafenib and identify predictive biomarkers to select patients more likely to benefit from sorafenib. The preclinical study by Zhang and celleagues published this month in BMC Medicine provides preliminary evidence that baseline phosphorylated extracellular signaling-regulated kinase (pERK) may be a relevant marker to reflect the level of constitutive activation of the RAF/mitogen-activated protein kinase kinase (MEK)/ERK signaling pathway and has the potential value in predicting response to sorafenib. The clinical data from the initial single arm phase II study and preliminary report from the randomized phase III study also suggest the correlation of baseline archived tumor pERK levels and time to tumor progression in HCC patients. Whether baseline pERK will prove to be a useful predictive biomarker of response and clinical benefits for sorafenib in HCC will need to be validated in future large prospective studies
Phosphorylation and Ubiquitination Regulate Protein Phosphatase 5 Activity and Its Prosurvival Role in Kidney Cancer
The serine/threonine protein phosphatase 5 (PP5) regulates multiple cellular signaling networks. A number of cellular factors, including heat shock protein 90 (Hsp90), promote the activation of PP5. However, it is unclear whether post-translational modifications also influence PP5 phosphatase activity. Here, we show an “on/off switch” mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90. Overexpression of the phosphomimetic T362E-PP5 mutant hyper-dephosphorylates substrates such as the co-chaperone Cdc37 and glucocorticoid receptor in cells. Our proteomic approach revealed that the tumor suppressor von Hippel-Lindau protein (VHL) interacts with and ubiquitinates K185/K199-PP5 for proteasomal degradation in a hypoxia- and prolyl-hydroxylation-independent manner. Finally, VHL-deficient clear cell renal cell carcinoma (ccRCC) cell lines and patient tumors exhibit elevated PP5 levels. Downregulation of PP5 causes ccRCC cells to undergo apoptosis, suggesting a prosurvival role for PP5 in kidney cancer
New Modularity of DAP-Kinases: Alternative Splicing of the DRP-1 Gene Produces a ZIPk-Like Isoform
DRP-1 and ZIPk are two members of the Death Associated Protein Ser/Thr Kinase
(DAP-kinase) family, which function in different settings of cell death
including autophagy. DAP kinases are very similar in their catalytic domains but
differ substantially in their extra-catalytic domains. This difference is
crucial for the significantly different modes of regulation and function among
DAP kinases. Here we report the identification of a novel alternatively spliced
kinase isoform of the DRP-1 gene, termed DRP-1β. The
alternative splicing event replaces the whole extra catalytic domain of DRP-1
with a single coding exon that is closely related to the sequence of the extra
catalytic domain of ZIPk. As a consequence, DRP-1β lacks the calmodulin
regulatory domain of DRP-1, and instead contains a leucine zipper-like motif
similar to the protein binding region of ZIPk. Several functional assays proved
that this new isoform retained the biochemical and cellular properties that are
common to DRP-1 and ZIPk, including myosin light chain phosphorylation, and
activation of membrane blebbing and autophagy. In addition, DRP-1β also
acquired binding to the ATF4 transcription factor, a feature characteristic of
ZIPk but not DRP-1. Thus, a splicing event of the DRP-1 produces a ZIPk like
isoform. DRP-1β is highly conserved in evolution, present in all known
vertebrate DRP-1 loci. We detected the corresponding mRNA and
protein in embryonic mouse brains and in human embryonic stem cells thus
confirming the in vivo utilization of this isoform. The
discovery of module conservation within the DAPk family members illustrates a
parsimonious way to increase the functional complexity within protein families.
It also provides crucial data for modeling the expansion and evolution of DAP
kinase proteins within vertebrates, suggesting that DRP-1 and ZIPk most likely
evolved from their ancient ancestor gene DAPk by two gene duplication events
that occurred close to the emergence of vertebrates