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Masashi Muramatsu, Lingqiu Gao, Jennifer Peresie, Benjamin Balderman, Shin Akakura, Irwin H Gelman
SSeCKS/Gravin/AKAP12 (SSeCKS) is a kinase scaffolding protein known to suppress metastasis by attenuating tumor-intrinsic PKC- and Src-mediated signaling pathways [1]. In addition to downregulation in metastatic cells, in silico analyses identified SSeCKS downregulation in prostate or breast cancer-derived stroma, suggesting a microenvironmental cell role in controlling malignancy. Although orthotopic B16F10 and SM1WT1[ Braf V600E ] mouse melanoma tumors grew similarly in syngeneic WT or SSeCKS-null (KO) mice, KO hosts exhibited 5- to 10-fold higher levels of peritoneal metastasis, and this enhancement could be adoptively transferred by pre-injecting naïve WT mice with peritoneal fluid (PF), but not non-adherent peritoneal cells (PC), from naïve KO mice...
September 19, 2017: Oncotarget
Wen Xie, Wei Su, Lijuan Zhang, Qingkun Shang, Bing Su
Metastasis remains the primary cause of prostate cancer related death. Cancer cells need to contact endothelial cells and disrupt endothelial junctions to cross the endothelium for invasion and metastasis. The suppression of heterotypic repulsion between cancer and endothelial cells allows cancer cells to invade into the surrounding tissue. Here, we demonstrate that SSeCKS/AKAP12 induced repulsion between human prostate cancer and microvessel endothelial cells, which was mediated by an angiogenesis inhibitor Semaphorin 3F...
September 2, 2017: Biochemical and Biophysical Research Communications
Natalya V Kaverina, Diana G Eng, Remington R S Schneider, Jeffrey W Pippin, Stuart J Shankland
The current studies used genetic fate mapping to prove that adult podocytes can be partially replenished following depletion. Inducible NPHS2-rtTA/tetO-Cre/RS-ZsGreen-R reporter mice were generated to permanently label podocytes with the ZsGreen reporter. Experimental focal segmental glomerulosclerosis (FSGS) was induced with a cytotoxic podocyte antibody. On FSGS day 7, immunostaining for the podocyte markers p57, synaptopodin, and podocin were markedly decreased by 44%, and this was accompanied by a decrease in ZsGreen fluorescence...
June 1, 2016: American Journal of Physiology. Renal Physiology
LingYan Zhang, Jianguo Shao, Feng Xiao, Lin Chen, Hongmei He
OBJECTIVE: To investigate the role of Src family kinases (Fgr, Hck, Lyn) and the major protein kinase C substrate SSeCKS in non-alcoholic steatohepatitis (NASH) and determine the possible mechanism regulating differential expression. METHODS: Kupffer cells were stimulated with CCL4 and effect on SSeCKS, Hck, Fgr, and Lyn expression was detected by real-time reverse transcription-PCR. Male Sprague-Dawley rats were used to create a NASH model by feeing a high fat diet...
May 2015: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
Yang Zhang, Xiaoke Nie, Tao Tao, Wenbo Qian, Shengyang Jiang, Junkang Jiang, Aihong Li, Aisong Guo, Guangfei Xu, Qiyun Wu
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental pollutant that could induce significant toxic effects in the human nervous system. However, the underlying molecular mechanism has not been entirely elucidated. Reactive astrogliosis has implicated in various neurological diseases via the production of a variety of pro-inflammatory mediators. Herein, we investigated the potential role of TCDD in facilitating astrocyte activation and the underlying molecular mechanisms. We showed that TCDD induced rapid astrocyte activation following TCDD exposure, which was accompanied by significantly elevated expression of Src-Suppressed-C Kinase Substrate (SSeCKS), a protein involved in protein kinase C (PKC)-mediated Nuclear Factor kappa B signaling, suggesting a possible involvement of PKC-induced SSeCKS activation in TCDD-triggered reactive astroglia...
June 2014: Journal of Neurochemistry
Meijuan Yan, Jianmei Zhao, Shunxin Zhu, Xiaoyi Shao, Li Zhang, Heng Gao, Dengfu Yao
Src-suppressed C kinase substrate (SSeCKS), an in vivo and in vitro protein kinase C substrate, is a major lipopolysaccharide (LPS) response protein which markedly upregulated in several organs, including brain, lung, heart, kidney etc., indicating a possible role of SSeCKS in inflammatory process. However, the expression and biological function of SSeCKS during neuronal inflammation remains to be elucidated, so we established an inflammatory model injected with LPS to investigate the gene expression patterns of SSeCKS in neural tissues by using TaqMan quantitative real-time PCR and immunohistochemistry in rat...
April 2014: Neurochemical Research
Hyun-Kyung Ko, Shin Akakura, Jennifer Peresie, David W Goodrich, Barbara A Foster, Irwin H Gelman
The emergence of recurrent, metastatic prostate cancer following the failure of androgen-deprivation therapy represents the lethal phenotype of this disease. However, little is known regarding the genes and pathways that regulate this metastatic process, and moreover, it is unclear whether metastasis is an early or late event. The individual genetic loss of the metastasis suppressor, SSeCKS/Gravin/AKAP12 or Rb, genes that are downregulated or deleted in human prostate cancer, results in prostatic hyperplasia...
February 1, 2014: Cancer Research
Tiangeng You, Yuanzhi Fan, Qi Li, Yong Gao, Yongkang Yang, Zhongxin Zhao, Congjun Wang
Recent reports suggest that src suppressed c kinase substrates (SSeCKS) are early inflammatory response protein. However, there is only scarce knowledge on the functional role of SSeCKS in liver under conditions of acute inflammation. In the present study, we investigated SSeCKS expression in liver after administration of carbon tetrachloride (CCl4) in rats and in isolated primary hepatic stellate cells (HSCs) upon activation on a plastic dish. We found that SSeCKS mRNA was hardly detectable in healthy liver tissue and further increased in carbon tetrachloride-mediated acute liver failure...
December 2013: Inflammation
Zahraa I Khamis, Kenneth A Iczkowski, Qing-Xiang Amy Sang
Despite advances in diagnosis and treatment of prostate cancer, development of metastases remains a major clinical challenge. Research efforts are dedicated to overcome this problem by understanding the molecular basis of the transition from benign cells to prostatic intraepithelial neoplasia (PIN), localized carcinoma, and metastatic cancer. Identification of proteins that inhibit dissemination of cancer cells will provide new perspectives to define novel therapeutics. Development of antimetastatic drugs that trigger or mimic the effect of metastasis suppressors represents new therapeutic approaches to improve patient survival...
September 2012: Medicinal Research Reviews
Shin Akakura, Irwin H Gelman
Cellular dynamics are controlled by key signaling molecules such as cAMP-dependent protein kinase (PKA) and protein kinase C (PKC). AKAP12/SSeCKS/Gravin (AKAP12) is a scaffold protein for PKA and PKC which controls actin-cytoskeleton reorganization in a spatiotemporal manner. AKAP12 also acts as a tumor suppressor which regulates cell-cycle progression and inhibits Src-mediated oncogenic signaling and cytoskeletal pathways. Reexpression of AKAP12 causes cell flattening, reorganization of the actin cytoskeleton, and the production of normalized focal adhesion structures...
2012: Journal of Signal Transduction
B Su, L Gao, F Meng, L-W Guo, J Rothschild, I H Gelman
Metastatic cell migration and invasion are regulated by altered adhesion-mediated signaling to the actin-based cytoskeleton via activated Src-FAK complexes. Src-suppressed C-kinase substrate (SSeCKS, the rodent orthologue of human Gravin/AKAP12), whose expression is downregulated by oncogenic Src and in many human cancers, antagonizes oncogenic Src pathways including those driving neovascularization at metastatic sites, metastatic cell motility and invasiveness. This is likely manifested through its function as a scaffolder of F-actin and signaling proteins such as cyclins, calmodulin, protein kinase C and A...
April 18, 2013: Oncogene
Irwin H Gelman
Scaffolding proteins such as SSeCKS/Gravin/AKAP12 ("AKAP12") are thought to control oncogenic signaling pathways by regulating key mediators in a spatiotemporal manner. The downregulation of AKAP12 in many human cancers, often associated with promoter hypermethylation, or the loss of its locus at 6q24-25.2, correlates with progression to malignancy and metastasis. The forced re-expression of AKAP12 in cancer cell lines suppresses in vitro parameters of oncogenic growth, invasiveness, and cell motility through its ability to scaffold protein kinase C (PKC), F-actin, cyclins, Src, and phosphoinositides, and possibly through additional scaffolding domains for PKA, calmodulin, β1,4-galactosyltransferase-polypeptide-1, β2-adrenergic receptors, and cAMP-specific 3',5'-cyclic phosphodiesterase 4D...
December 2012: Cancer Metastasis Reviews
Bettina Burnworth, Jeff Pippin, Prasanthi Karna, Shin Akakura, Ron Krofft, Guoqiang Zhang, Kelly Hudkins, Charles E Alpers, Kelly Smith, Stuart J Shankland, Irwin H Gelman, Peter J Nelson
Glomerular parietal epithelial cells (PECs) are precursors to podocytes in mature glomeruli; however, as progenitors, the distinct intrinsic mechanisms that allow for repeated periods of cell-cycle arrest and re-entry of PECs after glomerulogenesis are unknown. Here, we show that the Src-suppressed protein kinase C substrate (SSeCKS), a multivalent scaffolding A kinase anchoring protein, sequesters cyclin D1 in the cytoplasm of quiescent PECs. SSeCKS expression is induced in embryonic PECs, but not in embryonic podocytes, starting at the S phase of glomerulogenesis, and is constitutively expressed postnatally by PECs, but not podocytes, in normal glomeruli...
April 2012: Laboratory Investigation; a Journal of Technical Methods and Pathology
Li-Wu Guo, Lingqiu Gao, Julian Rothschild, Bing Su, Irwin H Gelman
The product of the SSeCKS/GRAVIN/AKAP12 gene ("SSeCKS") is a major protein kinase (PK) C substrate that exhibits tumor- and metastasis-suppressing activity likely through its ability to scaffold multiple signaling mediators such as PKC, PKA, cyclins, calmodulin, and Src. Although SSeCKS and PKCα bind phosphatidylserine, we demonstrate that phosphatidylserine-independent binding of PKC by SSeCKS is facilitated by two homologous SSeCKS motifs, EG(I/V)(T/S)XWXSFK(K/R)(M/L)VTP(K/R)K(K/R)X(K/R)XXXEXXXE(E/D) (amino acids 592-620 and 741-769)...
November 4, 2011: Journal of Biological Chemistry
Philip W Hinds
No abstract text is available yet for this article.
September 1, 2011: Cell Cycle
Irwin H Gelman
Emerging data suggest that SSeCKS/Gravin/AKAP12 ("AKAP12"), originally identified as an autoantigen in cases of myasthenia gravis, controls multiple biological processes through its ability to scaffold key signaling proteins such as protein kinase (PK) C and A, calmodulin, cyclins, phosphoinositides, "long" β-1,4 galactosyltransferase (GalTase) isoform, Src, as well as the actin cytoskeleton in a spatiotemporal manner. Specialized functions attributed to AKAP12 include the suppression of cancer malignancy, especially aspects of metastatic progression, regulation of blood-brain and blood-retina barrier formation, and resensitization of β2-adrenergic pain receptors...
November 2010: Genes & Cancer
Bai Shao, Chunmiao Li, Huiguang Yang, Aiguo Shen, Xiaohong Wu, Qin Yuan, Xiujie Wu, Lihua Kang, Zhiqiang Liu, Guowei Zhang, Xiang Lu, Chun Cheng
Src-suppressed C kinase substrate (SSeCKS), a protein kinase C substrate, is a major lipopolysaccharide (LPS) response protein. In addition, β-1,4 Galactosyltransferase-I (β-1,4-GalT-I) also plays an important role in the inflammation reactions of nervous system. It was reported that both SSeCKS and β-1,4-GalT-I were involved in the LPS-induced tumor necrosis factor-alpha (TNF-α) expression in rat primary astrocytes. However, the functional interaction between SSeCKS and β-1,4-GalT-I in the LPS-induced TNF-α secretion remains unclear...
October 2011: Cellular and Molecular Neurobiology
Shujuan Gao, Hsien-Yu Wang, Craig C Malbon
BACKGROUND: A-kinase-anchoring proteins, AKAPs, constitute a family of scaffolds that play an essential role in catalyzing the spatial-temporal, dynamic interactions of protein kinase A, protein kinase C, tyrosine kinases, G-protein-coupled receptors and ion channels. We studied AKAP5 (AKAP79; MW ~47 kDa) and AKAP12 (gravin, SSECKS; MW ~191 kDa) to probe if these AKAP scaffolds oligomerize. RESULTS: In gel analysis and sodium-dodecyl sulfate denaturation, AKAP12 behaved with a MW of a homo-dimer...
May 9, 2011: Journal of Molecular Signaling
Likun Zan, He Wu, Jie Jiang, Shiguang Zhao, Yuejia Song, Guoxin Teng, Heng Li, Ying Jia, Min Zhou, Xin Zhang, Jiping Qi, Jian Wang
A better understanding of the underlying mechanisms of angiogenesis and vascular permeability is necessary for the development of therapeutic strategies for ischemic injury. The purpose of this study was to examine the spatial and temporal expression of Src and Src-suppressed C kinase substrate (SSeCKS) in brain after middle cerebral artery occlusion (MCAO) and elucidate the relationships among Src, SSeCKS, and the key angiogenic factors present after stroke. Rats were subjected to either MCAO or sham operation...
July 2011: Neurochemistry International
Zahraa I Khamis, Kenneth A Iczkowski, Qing-Xiang Amy Sang
Despite advances in diagnosis and treatment of prostate cancer, development of metastases remains a major clinical challenge. Research efforts are dedicated to overcome this problem by understanding the molecular basis of the transition from benign cells to prostatic intraepithelial neoplasia (PIN), localized carcinoma, and metastatic cancer. Identification of proteins that inhibit dissemination of cancer cells will provide new perspectives to define novel therapeutics. Development of antimetastatic drugs that trigger or mimic the effect of metastasis suppressors represents new therapeutic approaches to improve patient survival...
January 16, 2011: Medicinal Research Reviews
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