A5069092547- Protein Kinase Regulation and GTPase Signaling
- Protein Tyrosine Phosphatases
- Melanoma and MAPK Pathways
- Glycosylation and Glycoproteins Research
- Galectins and Cancer Biology
- HER2/EGFR in Cancer Research
- Ubiquitin and proteasome pathways
- Genetic factors in colorectal cancer
- Cancer Mechanisms and Therapy
- Cellular transport and secretion
- Monoclonal and Polyclonal Antibodies Research
- RNA Interference and Gene Delivery
- Epigenetics and DNA Methylation
- Growth Hormone and Insulin-like Growth Factors
- Cancer-related Molecular Pathways
- Cytokine Signaling Pathways and Interactions
- Enzyme Structure and Function
- Colorectal Cancer Treatments and Studies
- Cell death mechanisms and regulation
- PI3K/AKT/mTOR signaling in cancer
- Cancer, Hypoxia, and Metabolism
- S100 Proteins and Annexins
- melanin and skin pigmentation
- Pancreatic function and diabetes
- Virus-based gene therapy research
University of Calgary
1998-2021
Health Sciences Centre
2000-2013
Friedrich Schiller University Jena
1999
The University of Melbourne
1996
Hong Kong University of Science and Technology
1996
University of Washington
1996
University of Hong Kong
1996
Foothills Medical Centre
1990
University of Toronto
1986-1989
Toronto General Hospital
1989
c-Src tyrosine kinase activity is elevated in several types of human cancer, and this has been attributed to expression levels, increased specific activity, activating mutations c-Src. We have found a number breast cancer cell lines with that also possess phosphatase directed against the carboxyl-terminal negative regulatory domain Src family kinases. To identify phosphatase, extracts from MDA-MB-435S cells were chromatographed fractions assayed for activity. Four peaks nonspecific substrate...
We have shown that a type I phosphatidylinositol (PI) kinase activity is associated with the epidermal growth factor (EGF) receptor in mouse fibroblast cell line expressing human EGF receptors (NRHER5) and this increases dramatically upon treatment of cells physiologically relevant concentrations EGF. stimulated time-dependent increase receptor-associated PI measured immunoprecipitates. Activation was detected 15 min after addition EGF, it peaked between 1 2 hr. as low 10 pM maximal...
Abstract Src-specific activity has been reported to be elevated in a high percentage of colon cancer cell lines and tumors, but the underlying mechanisms are largely unknown. In this study, we report that, seven tested, was (5.2- 18.7-fold) relative normal cells (FHC). This activation Src correlated with reduced phosphorylation at Y530 Src, whereas there no significant change level Y419. The membrane tyrosine phosphatase for family-specific phosphopeptide substrate FCP (Fyn COOH-terminal...
The MDA 468 human breast carcinoma cell line was examined for changes in epidermal growth factor (EGF) receptor synthesis and degradation under the influence of EGF. This used because it overexpresses EGF such that each has 10(6) receptors, but unlike well-studied A431 cell, its gene is amplified not rearranged. On exposure to EGF, total cellular protein, measured by immunoprecipitation with monoclonal antibody B1D8, reduced. half-life metabolically labeled L-[35S]methionine 24 h absence...
We have previously reported that both 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF) can stimulate the synthesis rate of EGF receptors. now show MDA468 breast cancer cells express mRNA for EGF-like molecule, transforming factor-alpha (TGF-alpha), demonstrate TPA or cause an accumulation receptor TGF-alpha mRNA. The levels paralleled our earlier protein data, with peak accumulations 2-3-fold 10(-9) M 3-5-fold 100 ng/ml seen between 6 8 h. A 7-fold was following 4...
Abstract —PP1 has previously been described as an inhibitor of the Src -family kinases p56 Lck and FynT. We have therefore decided to use PP1 determine functional role in platelet-derived growth factor (PDGF)–induced proliferation migration human coronary artery smooth muscle cells (HCASMCs). A synthetic protocol for PP1/AGL1872 developed, inhibitory activity against was examined. potently inhibited recombinant p60 c-src vitro -dependent tyrosine phosphorylation c-srcF572 -transformed NIH3T3...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTModulation of annexin II tetramer by tyrosine phosphorylationI. Hubaishy, P. G. Jones, J. Bjorge, C. Bellagamba, S. Fitzpatrick, D. Fujita, and M. WaismanCite this: Biochemistry 1995, 34, 44, 14527–14534Publication Date (Print):November 1, 1995Publication History Published online1 May 2002Published inissue 1 November 1995https://pubs.acs.org/doi/10.1021/bi00044a031https://doi.org/10.1021/bi00044a031research-articleACS PublicationsRequest reuse...
Previously, we and others have shown that epidermal growth factor (EGF) stimulates the synthesis of its own receptor accumulation EGF mRNA. Here, demonstrate tumor promotor, 12-O-tetradecanoylphorbol-13-acetate (TPA), like EGF, also in human breast carcinoma cell line, MDA468 cells. The rate increased 5-fold with a peak at 8 h after exposure to TPA half-maximal stimulation dose 5 ng/ml TPA. This occurred despite 30% decrease general cellular protein synthesis. resulted 60% more as determined...
Excitotoxicity resulting from overstimulation of glutamate receptors is a major cause neuronal death in cerebral ischemic stroke. The overstimulated ionotropic exert their neurotoxic effects part by overactivation calpains, which induce catalyzing limited proteolysis specific cellular proteins. Here, we report that cultured cortical neurons and vivo rat model focal stroke, the tyrosine kinase Src cleaved calpains at site N-terminal unique domain. This generates truncated fragment ~52 kDa,...
Src and signaling molecules downstream of Src, including signal transducer activator transcription 3 (Stat3) cMyc, have been implicated in the development, maintenance and/or progression several types human cancers, breast cancer. Here we report ability siRNA-mediated knock-down alone, simultaneous Stat3 cMyc to inhibit neoplastic phenotype a highly metastatic model cancer cell line, MDA-MB-435S, widely used for research.Src its partners were specifically targeted knocked-down using siRNA....
Although C-terminal Src kinase (CSK)-homologous (CHK) is generally believed to inactivate Src-family tyrosine kinases (SFKs) by phosphorylating their consensus regulatory (TyrT), exactly how CHK inactivates SFKs not fully understood. Herein, we report that in addition TyrT, can inhibit a novel non-catalytic mechanism. First, directly binds the SFK members Hck, Lyn, and form stable protein complexes. The complex formation mediated TyrT-independent mechanism because it occurs even absence of...
Two activated transforming mutants of human pp60c-src were found to possess single point mutations within the regulatory carboxyl terminus (E527K in CY CST201) and kinase domain (E381G WO CST1), respectively, that do not directly interfere with either c-Src (CSK) phosphorylation site (Tyr530) or SH2/3 domains. In vivo, both mutant proteins are hypophosphorylated on their carboxyl-terminal tyrosines hyperactive. an vitro Src inactivation assay, exhibited resistance by CSK relative wild-type...
The Src family of protein kinases (SFKs) mediates mitogenic signal transduction, and constitutive SFK activation is associated with tumorigenesis. To prevent activation, the catalytic activity SFKs in normal mammalian cells suppressed mainly by two inhibitors called C-terminal kinase (CSK) CSK-homologous (CHK), which inactivate phosphorylating a consensus tyrosine near C terminus (Y(T)). phosphorylated Y(T) intramolecularly binds to SH2 domain SFKs. This interaction, known as pY(T)/SH2...
The von Hippel-Lindau tumor suppressor protein (VHL), when mutated and inactivated, has been associated with renal CNS cancer development. VHL normally plays an important role in targeting for degradation of the HIF-1α (hypoxia inducible factor-1α) transcription factor, a primary positive regulator vascular endothelial growth factor (VEGF) production. In this report we demonstrate that destabilization can be induced by Src kinase may involved other cancers, including breast cancer. We have...
OBJECTIVE: Correlation between EGFR/HER2 protein levels and colon cancer prognosis has been suggested. However, reports on the prevalence of overexpression have divergent inconclusive due to technical variations. The uncertainty greatly affects decisions therapeutic interventions targeting both molecules. We aim at evaluating significance in cell lines. METHODS: employed normal epithelial strain FHC examined EGFR HER2 a series carcinoma lines using Western blotting, evaluated effectiveness...
In the present article we have examined if interaction of Ca2+-binding protein, annexin II tetramer (AIIt) with plasma membrane phospholipids or submembranous cytoskeleton, effects accessibility tyrosine phosphorylation site AIIt. presence Ca2+, pp60c-src catalyzed incorporation 0.22 ± 0.05 mol phosphate/mol AIIt (mean S.D., n = 5). The Ca2+-dependent binding to purified adrenal medulla phosphatidylserine vesicles stimulated pp60c-src-dependent 0.62 0.04 5) 0.93 0.07 5), respectively....
The INhibitor of Growth 1 (ING1) is stoichiometric member histone deacetylase (HDAC) complexes and functions as an epigenetic regulator a type II tumor suppressor. It impacts cell growth, aging, apoptosis, DNA repair, by affecting chromatin conformation gene expression. Down regulation mislocalization ING1 have been reported in diverse types Ser/Thr phosphorylation has implicated both these processes. Here we demonstrate that vitro vivo, the tyrosine kinase Src able to physically associate...
RNA interference has been used to dissect the importance of individual gene products in various human disease processes, including cancer. Small-interfering RNA, or siRNA, is one tools utilized this regard, but specially-designed delivery agents are required allow siRNA gain optimal access cell interior. Our laboratory two different siRNA-binding peptides containing a polyarginine core, and modified by myristoylation targeting motifs (iRGD Lyp-1). A third peptide was designed assist with...
Chicken embryo fibroblast cells overexpressing activated mutant forms of human pp60c-src, but not those normal exhibited high levels type I phosphatidylinositol (PI) kinase activity associated with pp60c-src. Levels PI were positively correlated src tyrosine protein and absolute Our results suggest that a linkage exists between certain pp60c-src the signal transduction pathway.
Abstract Inhibitors of PI3‐K/Akt are currently being assessed clinically in patients with advanced RCC . Identification therapeutic strategies that might enhance the efficacy inhibitors is therefore great interest. As PI3‐K inhibition would be expected to have many pro‐apoptotic effects, we hypothesized there may unique synergy between and BH 3‐mimetics. Towards this end, combination PI3K inhibitor LY 294002 Bcl‐2 family ABT ‐737 cell lines. We found combinatorial treatment these agents led...
The C-terminal src kinase (CSK) is a ubiquitously expressed, cytosolic enzyme capable of phosphorylating and inactivating several plasma membrane-bound src-family protein tyrosine kinases in vitro [Nada, S., Okada, M., MacAuley, A., Cooper, J. & Nakagawa, H. (1990) Nature 351, 69−72; Bergman, Mustelin, T., Oetken, C., Partanen, J., Flint, N. Amrein, K. E., Autero, Burn, P., Alitalo, (1992) EMBO 11, 2919−2924]. We purified CSK to apparent homogeneity from bovine thymus cytosol study how the...