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Linda M Parsons, Nicola A Grzeschik, Kasun Amaratunga, Peter Burke, Leonie M Quinn, Helena E Richardson
In both Drosophila melanogaster and mammalian systems, epithelial structure and underlying cell polarity are essential for proper tissue morphogenesis and organ growth. Cell polarity interfaces with multiple cellular processes that are regulated by the phosphorylation status of large protein networks. To gain insight into the molecular mechanisms that coordinate cell polarity with tissue growth, we screened a boutique collection of RNAi stocks targeting the kinome for their capacity to modify Drosophila "cell polarity" eye and wing phenotypes...
August 7, 2017: G3: Genes—Genomes—Genetics
Yusuke Nakatsu, Keiichi Mori, Yasuka Matsunaga, Takeshi Yamamotoya, Koji Ueda, Yuki Inoue, Keiko Mitsuzaki-Miyoshi, Hideyuki Sakoda, Midori Fujishiro, Suguru Yamaguchi, Akifumi Kushiyama, Hiraku Ono, Hisamitsu Ishihara, Tomoichiro Asano
The prolyl isomerase Pin1 binds to the phosphorylated Ser/Thr-Pro motif of target proteins and enhances their cis-trans conversion. This report is the first to show that Pin1 expression in pancreatic β cells is markedly elevated by high-fat diet feeding and in ob/ob mice. To elucidate the role of Pin1 in pancreatic β cells, we generated β-cell-specific Pin1 KO (βPin1 KO) mice. These mutant mice showed exacerbation of glucose intolerance but had normal insulin sensitivity. We identified two independent factors underlying impaired insulin secretion in the βPin1 KO mice...
July 14, 2017: Journal of Biological Chemistry
Chao-Nan Qian, Yan Mei, Jian Zhang
Metastasis is the major cause of treatment failure in cancer patients and of cancer-related deaths. This editorial discusses how cancer metastasis may be better perceived and controlled. Based on big-data analyses, a collection of 150 important pro-metastatic genes was studied. Using The Cancer Genome Atlas datasets to re-analyze the effect of some previously reported metastatic genes-e.g., JAM2, PPARGC1A, SIK2, and TRAF6-on overall survival of patients with renal and liver cancers, we found that these genes are actually protective factors for patients with cancer...
April 3, 2017: Chinese Journal of Cancer
Nicola J Darling, Rachel Toth, J Simon C Arthur, Kristopher Clark
The salt-inducible kinases (SIKs) control a novel molecular switch regulating macrophage polarization. Pharmacological inhibition of the SIKs induces a macrophage phenotype characterized by the secretion of high levels of anti-inflammatory cytokines, including interleukin (IL)-10, and the secretion of very low levels of pro-inflammatory cytokines, such as tumour necrosis factor α. The SIKs, therefore, represent attractive new drug targets for the treatment of macrophage-driven diseases, but which of the three isoforms, SIK1, SIK2 or SIK3, would be appropriate to target remains unknown...
February 15, 2017: Biochemical Journal
Johanna Säll, Annie M L Pettersson, Christel Björk, Emma Henriksson, Sebastian Wasserstrom, Wilhelm Linder, Yuedan Zhou, Ola Hansson, Daniel P Andersson, Mikael Ekelund, Eva Degerman, Karin G Stenkula, Jurga Laurencikiene, Olga Göransson
AIMS/HYPOTHESIS: Salt-inducible kinases (SIKs) are related to the metabolic regulator AMP-activated protein kinase (AMPK). SIK2 is abundant in adipose tissue. The aims of this study were to investigate the expression of SIKs in relation to human obesity and insulin resistance, and to evaluate whether changes in the expression of SIKs might play a causal role in the development of disturbed glucose uptake in human adipocytes. METHODS: SIK mRNA and protein was determined in human adipose tissue or adipocytes, and correlated to clinical variables...
February 2017: Diabetologia
Marc N Wein, Yanke Liang, Olga Goransson, Thomas B Sundberg, Jinhua Wang, Elizabeth A Williams, Maureen J O'Meara, Nicolas Govea, Belinda Beqo, Shigeki Nishimori, Kenichi Nagano, Daniel J Brooks, Janaina S Martins, Braden Corbin, Anthony Anselmo, Ruslan Sadreyev, Joy Y Wu, Kei Sakamoto, Marc Foretz, Ramnik J Xavier, Roland Baron, Mary L Bouxsein, Thomas J Gardella, Paola Divieti-Pajevic, Nathanael S Gray, Henry M Kronenberg
Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2...
October 19, 2016: Nature Communications
Kimberly E Maxfield, Jennifer Macion, Hariprasad Vankayalapati, Angelique W Whitehurst
Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with multiple, distinct molecular subtypes that exhibit unique transcriptional programs and clinical progression trajectories. Despite knowledge of the molecular heterogeneity of the disease, most patients are limited to generic, indiscriminate treatment options: cytotoxic chemotherapy, surgery, and radiation. To identify new intervention targets in TNBC, we used large-scale, loss-of-function screening to identify molecular vulnerabilities among different oncogenomic backgrounds...
December 15, 2016: Molecular and Cellular Biology
Jinhua Zhou, Albandri Alfraidi, Shu Zhang, Janice M Santiago-O'Farrill, Venkata Krishna Yerramreddy Reddy, Abdulkhaliq Alsaadi, Ahmed A Ahmed, Hailing Yang, Jinsong Liu, Weiqun Mao, Yan Wang, Hiroshi Takemori, Hariprasad Vankayalapati, Zhen Lu, Robert C Bast
Purpose: Salt-inducible kinase 2 (SIK2) is a centrosome kinase required for mitotic spindle formation and a potential target for ovarian cancer therapy. Here, we examine the effects of a novel small-molecule SIK2 inhibitor, ARN-3236, on sensitivity to paclitaxel in ovarian cancer.Experimental Design: SIK2 expression was determined in ovarian cancer tissue samples and cell lines. ARN-3236 was tested for its efficiency to inhibit growth and enhance paclitaxel sensitivity in cultures and xenografts of ovarian cancer cell lines...
April 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jacob A Galan, Joseph Avruch
The MST1 and MST2 protein kinases comprise the GCK-II subfamily of protein kinases. In addition to their amino-terminal kinase catalytic domain, related to that of the Saccharomyces cerevisiae protein kinase Ste20, their most characteristic feature is the presence near the carboxy terminus of a unique helical structure called a SARAH domain; this segment allows MST1/MST2 to homodimerize and to heterodimerize with the other polypeptides that contain SARAH domains, the noncatalytic polypeptides RASSF1-6 and Sav1/WW45...
October 4, 2016: Biochemistry
(no author information available yet)
A recent study reveals that the kinase SIK2 helps ovarian cancer cells metastasize and establish themselves in the fat-rich tissues of the abdominal cavity by promoting fatty-acid metabolism and cell proliferation. Mice bearing SIK2-overexpressing human ovarian cancer cells had larger, more abundant metastases than those whose tumors bore an inactive form of the kinase.
October 2016: Cancer Discovery
Jinwoo Lee, Takeshi Yamazaki, Hui Dong, Colin Jefcoate
The Steroidogenic acute regulatory protein (StAR) directs mitochondrial cholesterol uptake through a C-terminal cholesterol binding domain (CBD) and a 62 amino acid N-terminal regulatory domain (NTD) that contains an import sequence and conserved sites for inner membrane metalloproteases. Deletion of the NTD prevents mitochondrial import while maintaining steroidogenesis but with compromised cholesterol homeostasis. The rapid StAR-mediated cholesterol transfer in adrenal cells depends on concerted mRNA translation, p37 StAR phosphorylation and controlled NTD cleavage...
August 10, 2016: Molecular and Cellular Endocrinology
Fabrizio Miranda, David Mannion, Shujuan Liu, Yiyan Zheng, Lingegowda S Mangala, Clara Redondo, Sandra Herrero-Gonzalez, Ruoyan Xu, Charlotte Taylor, Donatien Fotso Chedom, Mohammad Karaminejadranjbar, Ashwag Albukhari, Dahai Jiang, Sunila Pradeep, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Eidarus Salah, Kamal R Abdul Azeez, Jonathan M Elkins, Leticia Campo, Kevin A Myers, Daniel Klotz, Serena Bivona, Sunanda Dhar, Robert C Bast, Hideyuki Saya, Hwan Geun Choi, Nathanael S Gray, Roman Fischer, Benedikt M Kessler, Christopher Yau, Anil K Sood, Takeshi Motohara, Stefan Knapp, Ahmed Ashour Ahmed
The adipocyte-rich microenvironment forms a niche for ovarian cancer metastasis, but the mechanisms driving this process are incompletely understood. Here we show that salt-inducible kinase 2 (SIK2) is overexpressed in adipocyte-rich metastatic deposits compared with ovarian primary lesions. Overexpression of SIK2 in ovarian cancer cells promotes abdominal metastasis while SIK2 depletion prevents metastasis in vivo. Importantly, adipocytes induce calcium-dependent activation and autophosphorylation of SIK2...
August 8, 2016: Cancer Cell
H-H Wang, C-Y Lin, S-H Su, C-T Chuang, Y-L Chang, T-Y Lee, S-C Lee, C-J Chang
Maintaining mesothelial cell viability is critical to long-term successful peritoneal dialysis (PD) treatment. To clarify the viability mechanism of peritoneal mesothelial cells under PD solutions exposure, we examined the mechanisms of cellular response to this stress conditions. Here we report that the proteasome activity is inhibited when treated with PD solutions. Proteasome inhibition-mediated activation of salt-inducible kinase 2 (SIK2), an endoplasmic reticulum-resident protein, is important for mesothelial cell viability...
2016: Cell Death & Disease
Yingyi Liu, Sujie Gao, Xuebo Chen, Meihan Liu, Cuiying Mao, Xuedong Fang
MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression through the endogenous RNA interference machinery. Treatments with combination of chemotherapy with surgery are essential for advanced-stage colorectal cancer. However, the development of chemoresistance is a major obstacle for clinical application of anticancer drugs. In this study, we report a miR-203-SIK2 axis that involves in the regulation of Taxol sensitivity in colon cancer cells. MiR-203 is downregulated in human colon tumor specimens and cell lines compared with their normal counterparts...
September 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Thomas B Sundberg, Yanke Liang, Huixian Wu, Hwan Geun Choi, Nam Doo Kim, Taebo Sim, Liv Johannessen, Adam Petrone, Bernard Khor, Daniel B Graham, Isabel J Latorre, Andrew J Phillips, Stuart L Schreiber, Jose Perez, Alykhan F Shamji, Nathanael S Gray, Ramnik J Xavier
Salt-inducible kinases (SIKs) are promising therapeutic targets for modulating cytokine responses during innate immune activation. The study of SIK inhibition in animal models of disease has been limited by the lack of selective small-molecule probes suitable for modulating SIK function in vivo. We used the pan-SIK inhibitor HG-9-91-01 as a starting point to develop improved analogs, yielding a novel probe 5 (YKL-05-099) that displays increased selectivity for SIKs versus other kinases and enhanced pharmacokinetic properties...
August 19, 2016: ACS Chemical Biology
Zhen-Ning Zhang, Lulu Gong, Sihan Lv, Jian Li, Xiaolu Tai, Wenqi Cao, Bing Peng, Shen Qu, Weida Li, Chao Zhang, Bing Luan
Fatty acid oxidation and subsequent ketogenesis is one of the major mechanisms to maintain hepatic lipid homeostasis under fasting conditions. Fasting hormone glucagon has been shown to stimulate ketone body production through activation of PPARα; however, the signal pathway linking glucagon to PPARα is largely undiscovered. Here we report that a SIK2-p300-PPARα cascade mediates glucagon's effect on ketogenesis. p300 interacts with PPARα through a conserved LXXLL motif and enhances its transcriptional activity...
March 17, 2016: Scientific Reports
Wen-Qi Du, Jun-Nian Zheng, Dong-Sheng Pei
INTRODUCTION: The salt-inducible kinases originally cloned in adrenal glands of high salt diet-fed rats, generally named as SIKs, are highly evolutionarily conserved serine/threonine protein kinases belonging to a family of AMP-activated protein kinase (AMPK). Overexpression of SIK2 and SIK3 is discovered in many tumors. Whereas, SIK1 expression was significantly lower in tumors than in normal tissues. AREAS COVERED: The main aim of our review is to introduce the signaling pathways as well as its mechanisms underlying their activity regulation, and especially the roles they play in cancer, which may shed light on the prospects of the cancer prevention and therapeutic targeting of SIKs in the future...
2016: Expert Opinion on Therapeutic Targets
David Curtis
For biological and statistical reasons it makes sense to combine information from variants at the level of the gene. One may wish to give more weight to variants which are rare and those that are more likely to affect function. A combined weighting scheme, implemented in the SCOREASSOC program, was applied to whole exome sequence data for 1392 subjects with schizophrenia and 982 with obesity from the UK10K project. Results conformed fairly well with null hypothesis expectations and no individual gene was strongly implicated...
January 2016: Annals of Human Genetics
Yumi Itoh, Masato Sanosaka, Hiroyuki Fuchino, Yasuhito Yahara, Ayako Kumagai, Daisaku Takemoto, Mai Kagawa, Junko Doi, Miho Ohta, Noriyuki Tsumaki, Nobuo Kawahara, Hiroshi Takemori
Salt-inducible kinases (SIKs), members of the 5'-AMP-activated protein kinase (AMPK) family, are proposed to be important suppressors of gluconeogenic programs in the liver via the phosphorylation-dependent inactivation of the CREB-specific coactivator CRTC2. Although a dramatic phenotype for glucose metabolism has been found in SIK3-KO mice, additional complex phenotypes, dysregulation of bile acids, cholesterol, and fat homeostasis can render it difficult to discuss the hepatic functions of SIK3. The aim of this study was to examine the cell autonomous actions of SIK3 in hepatocytes...
July 17, 2015: Journal of Biological Chemistry
Ya-Nan Li, Yi-Qun Cao, Xi Wu, Guo-Sheng Han, Lai-Xing Wang, Yu-Hui Zhang, Xin Chen, Bin Hao, Zhi-Jian Yue, Jian-Min Liu
BACKGROUND: PPP2R2C encodes a gamma isoform of the regulatory subunit B55 subfamily consisting PP2A heterotrimeric with A and C subunits. Currently, the precise functions of B55gamma in cancer are still under investigating. In this project, we reported a novel function of B55gamma in the regulation of glucose metabolism in Glioma cells. METHODS: Western blot and immunoprecipitation were performed to determine protein expression and interaction. Cell viability was measured by Typan Blue staining and direct cell counting using hematocytometer...
2015: Cancer Cell International
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