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C terminal Src kinase CSK in cancer

Yunshu Lu, Yipeng Yang, Yan Liu, Yajuan Hao, Yijian Zhang, Yunping Hu, Lin Jiang, Yurong Gong, Kejin Wu, Yingbin Liu
C-terminal Src kinase (Csk)-binding protein (Cbp) is a ubiquitously expressed transmembrane adaptor protein which regulating Src family kinase (SFK) activities. Although SFKs are well known for their involvement in breast cancer, the function of Cbp in breast carcinogenesis upon the adipose-tumor microenvironment has not been investigated. Here, we reported that adipose-derived mesenchymal stem cells (ASCs) induced increased expression of Cbp accompanied by enhanced cell proliferation and chemotherapy resistance in breast cancer cell MCF-7/ADR...
December 16, 2017: Biochemical and Biophysical Research Communications
Sushil Kumar, Bin Lu, Viralkumar Davra, Peter Hornbeck, Kazuya Machida, Raymond B Birge
The activity of Src family kinases (Src being the prototypical member) is tightly regulated by differential phosphorylation on Tyr416 (positive) and Tyr527 (negative), a duet that reciprocally regulates kinase activity. The latter negative regulation of Src on Tyr527 is mediated by C-terminal Src kinase (CSK) that phosphorylates Tyr527 and maintains Src in a clamped negative regulated state by promoting an intramolecular association. Here it is demonstrated that the SH2- and SH3-domain containing adaptor protein CrkII, by virtue of its phosphorylation on Tyr239, regulates the Csk/Src signaling axis to control Src activation...
January 2018: Molecular Cancer Research: MCR
Mengnan Zhang, Feng Ma, Ruyi Xie, Yao Wu, Meiyan Wu, Pei Zhang, Ying Peng, Jinjun Zhao, Jing Xiong, Aimin Li, Cheng Kequan, Yali Zhang, Side Liu, Jide Wang, Xueqing Chen
The adaptor protein Srcin1 is a novel Src-binding protein that regulates Src activation through C-terminal Src kinase (Csk). Srcin1 behaves as a tumour suppressor in breast cancer, but the role of Srcin1 in the development of colorectal cancer (CRC) remains unknown. In the present study, Srcin1 expression in normal tissue was examined by tissue microarray and assessed by immunohistochemistry in 10 patients. In addition, the biological impact of Srcin1 knockdown on CRC cells was investigated in vitro and in vivo...
May 2017: International Journal of Oncology
Tushar Tomar, Steven de Jong, Nicolette G Alkema, Rieks L Hoekman, Gert Jan Meersma, Harry G Klip, Ate Gj van der Zee, G Bea A Wisman
BACKGROUND: In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far...
October 20, 2016: Genome Medicine
Lu Xu, Xin Tong, Sujie Zhang, Fan Yin, Xiaoyan Li, Huafeng Wei, Cheng Li, Yajun Guo, Jian Zhao
Hepatocellular carcinoma (HCC) is the third leading cause of death in cancer patients worldwide. Understanding the molecular pathogenesis of HCC recurrence and chemoresistance is key to improving patients' prognosis. In this study, we report that downregulation of ASPP2, a member of the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region-containing protein (ASPP) family, bestowed HCC cells with stem-like properties and resistance to chemotherapy, including the expansion of side population fractions, formation of hepatospheroids, expression of stem cell-associated genes, loss of chemosensitivity, and increased tumorigenicity in immunodeficient mice...
October 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Jyoti Prasad Mishra, David Cohen, Andrea Zamperone, Dragana Nesic, Anne Muesch, Markus Stein
CagA is a multifunctional toxin of Helicobacter pylori that is secreted into host epithelial cells by a type IV secretion system. Following host cell translocation, CagA interferes with various host-cell signalling pathways. Most notably this toxin is involved in the disruption of apical-basolateral cell polarity and cell adhesion, as well as in the induction of cell proliferation, migration and cell morphological changes. These are processes that also play an important role in epithelial-to-mesenchymal transition and cancer cell invasion...
November 2015: Cellular Microbiology
Robert Roskoski
The physiological Src proto-oncogene is a protein-tyrosine kinase that plays key roles in cell growth, division, migration, and survival signaling pathways. From the N- to C-terminus, Src contains a unique domain, an SH3 domain, an SH2 domain, a protein-tyrosine kinase domain, and a regulatory tail. The chief phosphorylation sites of human Src include an activating pTyr419 that results from phosphorylation in the kinase domain by an adjacent Src molecule and an inhibitory pTyr530 in the regulatory tail that results from phosphorylation by C-terminal Src kinase (Csk) or Chk (Csk homologous kinase)...
April 2015: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Hailey J Kwon, Indrayani Waghmare, Shilpi Verghese, Aditi Singh, Amit Singh, Madhuri Kango-Singh
The Hippo signaling pathway is involved in regulating tissue size by inhibiting cell proliferation and promoting apoptosis. Aberrant Hippo pathway function is often detected in human cancers and correlates with poor prognosis. The Drosophila C-terminal Src kinase (d-Csk) is a genetic modifier of warts (wts), a tumor-suppressor gene in the Hippo pathway, and interacts with the Src oncogene. Reduction in d-Csk expression and the consequent activation of Src are frequently seen in several cancers including hepatocellular and colorectal tumors...
January 1, 2015: Developmental Biology
Qi Yao, Bing-Qian Liu, Hui Li, Deirdre McGarrigle, Bo-Wen Xing, Mao-Tian Zhou, Zhe Wang, J Jillian Zhang, Xin-Yun Huang, Lin Guo
Protein-tyrosine kinase C-terminal Src kinase (Csk) was originally purified as a kinase for phosphorylating Src and other Src family kinases. The phosphorylation of a C-terminal tyrosine residue of Src family kinases suppresses their kinase activity. Therefore, most physiological studies regarding Csk function have been focused on Csk as a negative regulator of Src family tyrosine kinases and as a potential tumor suppressor. Paradoxically, the protein levels of Csk were elevated in some human carcinomas. In this report, we show that eukaryotic elongation factor 2 (eEF2) is a new protein substrate of Csk and could locate in the nucleus...
May 2, 2014: Journal of Biological Chemistry
Kentaro Kajiwara, Takayuki Yamada, Takeshi Bamba, Eiichiro Fukusaki, Fumio Imamoto, Masato Okada, Chitose Oneyama
The proto-oncogenic tyrosine kinase c-Src is up-regulated in various human cancers, implicating its role in tumour progression. Upon activation, c-Src translocates to focal adhesions and initiates intracellular signalling cascades that promote malignant transformation, but the underlying mechanisms for c-Src translocation remain unclear. In the present study we show that c-Src up-regulation perturbs sphingolipid/cholesterol-enriched membrane microdomains by activating ceramide synthesis, resulting in promotion of c-Src translocation...
February 15, 2014: Biochemical Journal
M Hrdinka, V Horejsi
Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), also known as Csk-binding protein (Cbp), is a ubiquitously expressed transmembrane adaptor protein present in lipid rafts and involved in a number of signaling pathways. It helps recruit cytoplasmic C-terminal Src kinase (Csk) to lipid raft-associated Src kinases, mediates a link to actin cytoskeleton and interacts with several other important cytoplasmic and plasma membrane-associated proteins. In recent years, PAG has been implicated in various aspects of cancer cell biology...
October 9, 2014: Oncogene
Nanaocha Sharma, Daniele Repetto, Simona Aramu, Silvia Grasso, Isabella Russo, Arianna Fiorentino, Maurizia Mello-Grand, Sara Cabodi, Vijay Singh, Giovanna Chiorino, Emilia Turco, Paola Di Stefano, Paola Defilippi
p140Cap is an adaptor protein that negatively controls tumor cell properties, by inhibiting in vivo tumor growth and metastasis formation. Our previous data demonstrated that p140Cap interferes with tumor growth and impairs invasive properties of cancer cells inactivating signaling pathways, such as the tyrosine kinase Src or E-cadherin/EGFR cross-talk. In breast cancer p140Cap expression inversely correlates with tumor malignancy. p140Cap is composed of several conserved domains that mediate association with specific partners...
2013: American Journal of Cancer Research
Shakir M Saud, Matthew R Young, Yava L Jones-Hall, Lilia Ileva, Moses O Evbuomwan, Jennifer Wise, Nancy H Colburn, Young S Kim, Gerd Bobe
Analysis of the Polyp Prevention Trial showed an association between an isorhamnetin-rich diet and a reduced risk of advanced adenoma recurrence; however, the mechanism behind the chemoprotective effects of isorhamnetin remains unclear. Here, we show that isorhamnetin prevents colorectal tumorigenesis of FVB/N mice treated with the chemical carcinogen azoxymethane and subsequently exposed to colonic irritant dextran sodium sulfate (DSS). Dietary isorhamnetin decreased mortality, tumor number, and tumor burden by 62%, 35%, and 59%, respectively...
September 1, 2013: Cancer Research
Rhiannon J Whiting, Christine J Payne, Jiulia Satiaputra, Nicole Kucera, Theresa W Qiu, Sevgi Irtegun, Natalie J Gunn, Neli S Slavova-Azmanova, Neli S Lavova-Azmanova, Terrence D Mulhern, Evan Ingley
The tyrosine kinase Lyn is involved in oncogenic signalling in several leukaemias and solid tumours, and we have previously identified a pathway centred on Cbp [Csk (C-terminal Src kinase)-binding protein] that mediates both enzymatic inactivation, as well as proteasomal degradation of Lyn via phosphorylation-dependent recruitment of Csk (responsible for phosphorylating the inhibitory C-terminal tyrosine of Lyn) and SOCS1 (suppressor of cytokine signalling 1; an E3 ubiquitin ligase). In the present study we show that fusing specific functional motifs of Cbp and domains of SOCS1 together generates a novel molecule capable of directing the proteasomal degradation of Lyn...
March 15, 2012: Biochemical Journal
Shudong Zhu, Donald J Fujita, Jerry H C Wang
Src family kinase (SFK) is a family of protein tyrosine kinases that play important roles in the development of various cancers. Here, we showed that a naturally occurring inhibitory factor of SFK can be extracted from the rat brain. This inhibitor strongly suppressed the activity of SFKs including Lck and Fyn. It did not inhibit other protein tyrosine kinases including Wee1 or serine/threonine kinases Mst2, Cdk5/p25, Cdk5/p35, and Cdk2/cyclin A. The inhibitor was not an ATPase, a phosphatase that dephosphorylates substrates of the SFK reaction, or a protease that degrades SFKs...
August 2012: Journal of Enzyme Inhibition and Medicinal Chemistry
Asal Fallah-Tafti, Rakesh Tiwari, Amir Nasrolahi Shirazi, Tahmineh Akbarzadeh, Deendayal Mandal, Abbas Shafiee, Keykavous Parang, Alireza Foroumadi
Src kinase mutations and/or overexpression have been implicated in the development of a number of human cancer including colon, breast, and lung cancers. Thus, designing potent and selective Src kinase inhibitors as anticancer agents is a subject of major interest. A series of 4-aryl substituted derivatives of 2-amino-7-dimethylamino-4H-chromene-3-carbonitrile were synthesized using one-pot reaction of appropriate substituted aromatic aldehydes, malononitrile, and 3-(dimethylamino)phenol in the presence of piperidine...
September 2011: Medicinal Chemistry
Liudmilla Rubbi, Björn Titz, Lauren Brown, Erica Galvan, Evangelia Komisopoulou, Sharon S Chen, Tracey Low, Martik Tahmasian, Brian Skaggs, Markus Müschen, Matteo Pellegrini, Thomas G Graeber
In subtypes and late stages of leukemias driven by the tyrosine kinase fusion protein Bcr-Abl, signaling by the Src family kinases (SFKs) critically contributes to the leukemic phenotype. We performed global tyrosine phosphoprofiling by quantitative mass spectrometry of Bcr-Abl-transformed cells in which the activities of the SFKs were perturbed to build a detailed context-dependent network of cancer signaling. Perturbation of the SFKs Lyn and Hck with genetics or inhibitors revealed Bcr-Abl downstream phosphorylation events either mediated by or independent of SFKs...
March 29, 2011: Science Signaling
Kei Suzuki, Chitose Oneyama, Hironobu Kimura, Shoji Tajima, Masato Okada
The transmembrane adaptor protein Cbp (or PAG1) functions as a suppressor of Src-mediated tumor progression by promoting the inactivation of Src. The expression of Cbp is down-regulated in Src-transformed cells and in various human cancer cells, suggesting a potential role for Cbp as a tumor suppressor. However, the mechanisms underlying the down-regulation of Cbp remain unknown. The present study shows that Cbp expression is down-regulated by epigenetic histone modifications via the MAPK/PI3K pathway. In mouse embryonic fibroblasts, transformation by oncogenic Src and Ras induced a marked down-regulation of Cbp expression...
May 6, 2011: Journal of Biological Chemistry
D J Shields, E A Murphy, J S Desgrosellier, A Mielgo, S K M Lau, L A Barnes, J Lesperance, M Huang, C Schmedt, D Tarin, A M Lowy, D A Cheresh
Pancreas cancer is one of the most lethal malignancies and is characterized by activating mutations of Kras, present in 95% of patients. More than 60% of pancreatic cancers also display increased c-Src activity, which is associated with poor prognosis. Although loss of tumor suppressor function (for example, p16, p53, Smad4) combined with oncogenic Kras signaling has been shown to accelerate pancreatic duct carcinogenesis, it is unclear whether elevated Src activity contributes to Kras-dependent tumorigenesis or is simply a biomarker of disease progression...
May 5, 2011: Oncogene
Takashi Kanou, Chitose Oneyama, Kunimitsu Kawahara, Akira Okimura, Mitsunori Ohta, Naoki Ikeda, Yasushi Shintani, Meinoshin Okumura, Masato Okada
The tyrosine kinase c-Src is upregulated in various human cancers, although the precise regulatory mechanism underlying this upregulation is unclear. We previously reported that a transmembrane adaptor Csk-binding protein (Cbp; PAG1) plays an important role in controlling the cell transformation that is induced by the activation of c-Src. To elucidate the in vivo role of Cbp, we examined the function of Cbp in lung cancer cell lines and tissues. In this study, we found that Cbp was markedly downregulated in human non-small cell lung cancer (NSCLC) cells...
January 2011: Molecular Cancer Research: MCR
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