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Crk-associated substrate tyrosine phosphorylation sites are critical for invasion and metastasis of SRC-transformed cells.
Brábek J, Constancio SS, Siesser PF, Shin NY, Pozzi A, Hanks SK
(2005) Mol Cancer Res 3: 307-15
MeSH Terms: Animals, Binding Sites, Cell Line, Transformed, Cell Movement, Cells, Cultured, Collagen, Cytoskeletal Proteins, Drug Combinations, Enzyme Activation, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Genes, src, Injections, Subcutaneous, Laminin, Lung Neoplasms, Matrix Metalloproteinase 2, Mice, Mice, Nude, Neoplasm Invasiveness, Neoplasm Transplantation, Oncogene Protein v-crk, Paxillin, Phosphoproteins, Phosphorylation, Protein-Tyrosine Kinases, Proteoglycans, Retroviridae Proteins, Oncogenic, Tyrosine, src Homology Domains
Show Abstract · Added February 24, 2014
Crk-associated substrate (CAS, p130Cas) is a major tyrosine phosphorylated protein in cells transformed by v-crk and v-src oncogenes. We recently reported that reexpression of CAS in CAS-deficient mouse embryo fibroblasts transformed by oncogenic Src promoted an invasive phenotype associated with enhanced cell migration through Matrigel, organization of actin into large podosome ring and belt structures, activation of matrix metalloproteinase-2, and elevated tyrosine phosphorylation of the focal adhesion proteins FAK and paxillin. We have now extended these studies to examine the mechanism by which CAS achieves these changes and to evaluate the potential role for CAS in promoting in vivo tumor growth and metastasis. Whereas the presence or absence of CAS did not alter the primary growth of subcutaneous-injected Src-transformed mouse embryo fibroblasts, CAS expression was required to promote lung metastasis following removal of the primary tumor. The substrate domain YxxP tyrosines, the major sites of CAS phosphorylation by Src that mediate interactions with Crk, were found to be critical for promoting both invasive and metastatic properties of the cells. The ability of CAS to promote Matrigel invasion, formation of large podosome structures, and tyrosine phosphorylation of Src substrates, including FAK, paxillin, and cortactin, was also strictly dependent on the YxxP tyrosines. In contrast, matrix metalloproteinase-2 activation was most dependent on the CAS SH3 domain, whereas the substrate domain YxxP sites also contributed to this property. Thus multiple CAS-mediated signaling events are implicated in promoting invasive and metastatic properties of Src-transformed cells.
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29 MeSH Terms
Crk-associated substrate p130(Cas) interacts with nephrocystin and both proteins localize to cell-cell contacts of polarized epithelial cells.
Donaldson JC, Dempsey PJ, Reddy S, Bouton AH, Coffey RJ, Hanks SK
(2000) Exp Cell Res 256: 168-78
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Cell Line, Cell Polarity, Cell Transformation, Neoplastic, Crk-Associated Substrate Protein, Dogs, Epithelial Cells, Genes, src, Humans, Intercellular Junctions, Kidney, Membrane Proteins, Mice, Molecular Sequence Data, Oncogene Protein v-crk, Phosphoproteins, Proteins, Recombinant Proteins, Retinoblastoma Protein, Retinoblastoma-Like Protein p130, Retroviridae Proteins, Oncogenic, Reverse Transcriptase Polymerase Chain Reaction, Sequence Alignment, Sequence Homology, Amino Acid, Transcription, Genetic, Transfection, src Homology Domains
Show Abstract · Added March 27, 2014
Crk-associated substrate (p130(Cas), Cas) is a docking protein first recognized as having elevated phosphotyrosine content in mammalian cells transformed by v-Src and v-Crk oncoproteins. Subsequent studies have implicated Cas in the control of normal cell behavior through its roles in integrin-mediated signal transduction and organization of the actin cytoskeleton at sites of cell adhesion. In this study, we sought to gain new insight into normal Cas function by identifying previously unrecognized interacting proteins. A yeast two-hybrid screen using the C-terminal region of Cas as a bait identified the Src homology 3 (SH3) domain of the mouse "nephrocystin" protein-orthologous to a human protein whose loss of function leads to the cystic kidney disease familial juvenile nephronophthisis. The putative full-length mouse and partial canine nephrocystin sequences were deduced from cDNA clones. Additional studies using epitope-tagged mouse nephrocystin indicated that nephrocystin and Cas can interact in mammalian cells and revealed that both proteins prominently localize at or near sites of cell-cell contact in polarized Madin-Darby canine kidney epithelial cells. Our findings provide novel insight into the normal cellular activities regulated by both Cas and nephrocystin, and raise the possibility that these proteins have a related function in polarized epithelial cells.
Copyright 2000 Academic Press.
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29 MeSH Terms
Prostaglandin A2 blocks the activation of G1 phase cyclin-dependent kinase without altering mitogen-activated protein kinase stimulation.
Hitomi M, Shu J, Strom D, Hiebert SW, Harter ML, Stacey DW
(1996) J Biol Chem 271: 9376-83
MeSH Terms: 3T3 Cells, Animals, Calcium-Calmodulin-Dependent Protein Kinases, Cell Cycle, Cell Transformation, Neoplastic, Cyclin-Dependent Kinases, Enzyme Activation, G1 Phase, G2 Phase, Kinetics, Mice, Microinjections, Mitosis, Oncogene Proteins v-raf, Oncogenes, Phosphorylation, Prostaglandins A, Retinoblastoma Protein, Retroviridae Proteins, Oncogenic, Time Factors, ras Proteins
Show Abstract · Added June 10, 2010
Prostaglandin A2 (PGA2) reversibly blocked the cell cycle progression of NIH 3T3 cells at G1 and G2/M phase. When it was applied to cells synchronized in G0 or S phase, cells were blocked at G1 and G2/M, respectively. The G2/M blockage was transient. Microinjected oncogenic leucine 61 Ras protein could not override the PGA2 induced G1 blockage, nor could previous transformation with the v-raf oncogene. The serum-induced activation of mitogen-activated protein kinase was not inhibited by PGA2 treatment. These data suggest that PGA2 blocks cell cycle progression without interfering with the cytosolic proliferative signaling pathway. Combined microinjection of E2F-1 and DP-1 proteins or microinjected adenovirus E1A protein, however, could induce S phase in cells arrested in G1 by PGA2, indicating that PGA2 does not directly inhibit the process of DNA synthesis. In quiescent cells, PGA2 blocked the normal hyperphosphorylation of the retinoblastoma susceptible gene product and the activation of cyclin-dependent kinase (CDK) 2 and CDK4, in response to serum stimulation. PGA2 treatment elevated the p21Waf1/Cip1/Sdi1 protein expression level. These data indicate that PGA2 may arrest the cell cycle in G1 by interfering with the activation of G1 phase CDKs.
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21 MeSH Terms
Activation of hepatic proliferation-associated transcription factors by lipopolysaccharide.
Beauchamp RD, Papaconstantinou J, Henderson AM, Sheng HM, Townsend CM, Thompson JC
(1994) Surgery 116: 367-76; discussion 376-7
MeSH Terms: Animals, Base Sequence, DNA-Binding Proteins, Early Growth Response Protein 1, Genes, Immediate-Early, Immediate-Early Proteins, Lipopolysaccharides, Liver, Male, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Proto-Oncogene Proteins c-jun, RNA, Messenger, Retroviridae Proteins, Oncogenic, Transcription Factors
Show Abstract · Added May 3, 2013
BACKGROUND - The hepatic acute-phase response is the result of reprogramming of gene expression in the liver. Similar acute-phase responses occur in regenerating liver after partial hepatectomy and are preceded by increases in the expression of a set of transcriptional regulatory proteins that are encoded by "immediate-early" genes. The purpose of this study was to determine whether acute systemic inflammation after lipopolysaccharide injection induces hepatic immediate-early genes that are induced by partial hepatectomy.
METHODS - Two- to 4-month-old Balb/c mice received intraperitoneal Escherichia coli lipopolysaccharide (0111:B4; 100 micrograms), and total liver RNA, nuclear protein extracts, or total liver protein lysates were obtained at 0, 1, 3, 12, and 24 hours. RNA blot hybridization analysis was used to determine steady-state messenger RNA levels for c-jun, jun-B, jun-D, c-fos, fos-B, fra-1, nup475, and zif268. Specific nuclear protein-binding activity was determined by gel mobility shift assay. The protein c-Jun was detected by antibody-blocking experiments, and Jun-B was detected by gel supershift assay of the activating protein (AP-1) complex. Steady-state Jun-B levels were determined by immunoblot analysis.
RESULTS - Intraperitoneal injection of lipopolysaccharide is followed by induction (from fivefold to 13-fold) of c-jun, jun-B, c-fos, zif268, and nup475 messenger RNAs in the liver. Lipopolysaccharide induced increases in AP-1 and Zif268 consensus DNA-binding activity in mouse liver. The proteins c-Jun and Jun-B are detected in the AP-1 complex after administration of lipopolysaccharide.
CONCLUSIONS - The induction of hepatic immediate-early genes after lipopolysaccharide is similar to that that follows partial hepatectomy. These transcription factors likely have important roles in the reprogramming of gene expression that leads to the acute-phase response.
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16 MeSH Terms
Melanoma growth stimulatory activity signaling through the class II interleukin-8 receptor enhances the tyrosine phosphorylation of Crk-associated substrate, p130, and a 70-kilodalton protein.
Schraw W, Richmond A
(1995) Biochemistry 34: 13760-7
MeSH Terms: Antigens, CD, Blotting, Western, Cell Line, Cell Membrane, Chemokine CXCL1, Chemokines, CXC, Chemotactic Factors, Crk-Associated Substrate Protein, Cytosol, Growth Substances, Humans, Intercellular Signaling Peptides and Proteins, Melanoma, Molecular Weight, Neoplasm Proteins, Oncogene Protein v-crk, Phosphoproteins, Phosphorylation, Phosphotransferases, Placenta, Proteins, Receptors, Interleukin, Receptors, Interleukin-8A, Retinoblastoma-Like Protein p130, Retroviridae Proteins, Oncogenic, Serine, Transfection, Tyrosine
Show Abstract · Added May 30, 2013
Binding of the CXC chemokine, melanoma growth stimulatory activity (MGSA), to the class II IL-8 receptor on cells which overexpress this G-protein coupled receptor results in enhanced phosphorylation on serine residues. In experiments described herein, it is demonstrated that MGSA also enhances the tyrosine phosphorylation of two endogenously tyrosine phosphorylated proteins approximately 130 and 70 kDa in size. MGSA treatment (5 nM) of the clonally selected, stably transfected placental cell line, 3ASubE P-3, which overexpresses the class II IL-8 receptor, results in the maximal tyrosine phosphorylation of the 130 kDa protein before 2 min. This enhanced phosphorylation of the 130 kDa protein returns to basal level after a 5 min treatment. Based upon cell fractionation studies, the 130 kDa protein is concentrated in the membrane fraction of the cells. The 70 kDa protein which also shows tyrosine phosphorylation is predominantly cytosolic. The identity of the 130 kDa tyrosine phosphorylated protein was determined by immunoprecipitation and Western blot analyses. In these experiments, the 130 kDa tyrosine phosphorylated protein was shown to immunoprecipitate with antibody to the cas antigen (crk-associated substrate) and with antibody to the p130 tyrosine phosphorylated protein described as undergoing tyrosine phosphorylation in src transformed cells. The data suggest that MGSA binding to the class II IL-8 receptor is associated with tyrosine phosphorylation of p130/cas. The data also suggest that p130 and the cas antigen are the same protein.
2 Communities
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28 MeSH Terms
Protein kinase C phosphorylates pp60src at a novel site.
Gould KL, Woodgett JR, Cooper JA, Buss JE, Shalloway D, Hunter T
(1985) Cell 42: 849-57
MeSH Terms: Amino Acid Sequence, Animals, Avian Sarcoma Viruses, Brain, Cells, Cultured, Kinetics, Mice, Muscles, Oncogene Protein pp60(v-src), Phosphorylation, Protein Kinase C, Protein Kinases, Rabbits, Rats, Retroviridae Proteins, Serine, Substrate Specificity, Tetradecanoylphorbol Acetate
Show Abstract · Added March 5, 2014
The transforming protein of Rous sarcoma virus (pp60v-src) and its normal cellular homolog (pp60c-src) are demonstrated to be phosphorylated at serine 12 in vivo under certain conditions. We propose that protein kinase C is responsible for this modification based on the following evidence. First, the tumor promoters, 12-O-tetradecanoylphorbol-13-acetate and teleocidin, and synthetic diacylglycerol, known activators of protein kinase C in vivo, cause nearly complete phosphorylation of pp60src at serine 12. Second, among five purified serine/threonine-specific protein kinases tested, only protein kinase C phosphorylates pp60c-src and pp60v-src in vitro at serine 12. Third, purified protein kinase C phosphorylates a synthetic peptide corresponding to the N-terminal 20 amino acids of pp60c-src at serine 12. The physiological significance of this novel phosphorylation is discussed.
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18 MeSH Terms
Cell surface expression and orientation in membranes of the 44-amino-acid SH protein of simian virus 5.
Hiebert SW, Richardson CD, Lamb RA
(1988) J Virol 62: 2347-57
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Viral, Capsid, Cell Line, Chlorocebus aethiops, Fibroblasts, Kidney, Membrane Proteins, Molecular Sequence Data, Respirovirus, Retroviridae Proteins, Oncogenic
Show Abstract · Added June 10, 2010
Antiserum was raised against a synthetic peptide containing the N-terminal hydrophilic domain of the small hydrophobic protein (SH) of simian virus 5 (SV5) and used to characterize properties of the SH protein. SH demonstrated properties of an integral membrane protein. Indirect immunofluorescence experiments showed that the protein is involved in the exocytotic pathway, and isolation of plasma membranes from SV5-infected cells showed an enrichment of SH, indicating that SH is transported to the infected-cell surface. Biochemical analysis of the orientation of SH in membranes by proteolysis of intact SV5-infected cell surfaces and intracellular microsomal vesicles indicated that SH is oriented in membranes with its N-terminal hydrophilic domain exposed on the cytoplasmic face of the plasma membrane and the C terminus of approximately five amino acid residues exposed at the cell surface. These data are discussed with respect to positive-acting signals being necessary in the ectodomain of SH for cell surface expression.
1 Communities
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12 MeSH Terms
Activation of the oncogenic potential of the avian cellular src protein by specific structural alteration of the carboxy terminus.
Reynolds AB, Vila J, Lansing TJ, Potts WM, Weber MJ, Parsons JT
(1987) EMBO J 6: 2359-64
MeSH Terms: Amino Acid Sequence, Animals, Avian Sarcoma Viruses, Cell Transformation, Neoplastic, Cells, Cultured, Chick Embryo, Cloning, Molecular, DNA Restriction Enzymes, Genetic Vectors, Oncogene Protein pp60(v-src), Protein-Tyrosine Kinases, Retroviridae Proteins
Show Abstract · Added March 5, 2014
The role of tyrosine phosphorylation in the regulation of tyrosine protein kinase activity was investigated using site-directed mutagenesis to alter the structure and environment of the three tyrosine residues present in the C terminus of avian pp60c-src. Mutations that change Tyr 527 to Phe or Ser activate in vivo tyrosine protein kinase activity and induce cellular transformation of chicken cells in culture. In contrast, alterations of tyrosine residues present at positions 511 or 519 in c-src do not induce transformation or in vivo tyrosine protein kinase activity. Amber mutations, which alter the structure of the pp60c-src C terminus by inducing premature termination of the c-src protein at either residue 518 or 523 also induce morphological transformation and increase in vivo tyrosine phosphorylation, whereas removal of the last four residues of c-src by chain termination at residue 530 does not alter the kinase activity or the biological activity of the resultant c-src protein. We conclude from these studies that C-terminal alterations which either remove or replace Tyr 527 serve to activate the c-src protein resulting in cellular transformation and increased in vivo tyrosine protein kinase activity.
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12 MeSH Terms
Stable association of activated pp60src with two tyrosine-phosphorylated cellular proteins.
Reynolds AB, Kanner SB, Wang HC, Parsons JT
(1989) Mol Cell Biol 9: 3951-8
MeSH Terms: Animals, Antibodies, Monoclonal, Avian Sarcoma Viruses, Chick Embryo, Enzyme Activation, Molecular Weight, Mutation, Oncogene Protein pp60(v-src), Phosphoproteins, Phosphorylation, Phosphotyrosine, Protein Kinases, Retroviridae Proteins, Transformation, Genetic, Tyrosine
Show Abstract · Added March 5, 2014
We have identified two phosphotyrosine-containing cellular proteins with relative molecular masses of 130,000 (pp130) and 110,000 (pp110) daltons in chicken embryo cells that coimmunoprecipitated with pp60v-src and activated forms of chicken pp60c-src (pp60(527)F). Most if not all of the tyrosine-phosphorylated forms of pp130 and pp110 could be immunoprecipitated from lysates with any of several src protein-specific monoclonal antibodies directed against at least three spatially distinct epitopes. Consequently, of the more than 15 prominent phosphoproteins detected on immunoblots with phosphotyrosine-specific antibodies, pp130 and pp110 were selectively removed by src protein-specific immunoprecipitation, and their presence in the immunoprecipitates appears to have been due to a direct interaction with activated src proteins. src protein variants that induce different morphological phenotypes were altered in their ability to form detergent-stable complexes with pp130 and pp110 or with pp110 alone. Mutant src proteins, defective for myristylation, showed increased tyrosine phosphorylation of and association with pp110. Expression of src variants with mutations in the A box (pp60dl92/527F) or B box (pp60dl155/527F) of the src homology region induced differences in phosphorylation of pp130 and pp110, as well as changes in their association with variant src proteins. Sequences within the B-box region appeared to be necessary for stable complex formation with pp130 and pp110 and may be involved in the interaction of activated src proteins with cellular substrates.
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15 MeSH Terms
Radiosensitivity of small-cell lung cancer xenografts compared with activity of c-myc, N-myc, L-myc, c-raf-1 and K-ras proto-oncogenes.
Rygaard K, Slebos RJ, Spang-Thomsen M
(1991) Int J Cancer 49: 279-84
MeSH Terms: Animals, Carcinoma, Small Cell, Gene Expression Regulation, Neoplastic, Genes, myc, Genes, ras, Lung Neoplasms, Mice, Mice, Nude, Neoplasm Transplantation, Oncogene Proteins v-raf, RNA, Messenger, RNA, Neoplasm, Radiation Tolerance, Retroviridae Proteins, Oncogenic
Show Abstract · Added March 5, 2014
Oncogenes of the myc family c-raf-1 and K-ras have been reported to modulate radiosensitivity. We examined the possible relationship between in vivo radiosensitivity to single-dose irradiation with 3-10 Gy, and activity of these proto-oncogenes in 2 sets of small-cell lung cancer (SCLC) xenografts, the CPH and the GLC series. CPH-54A and CPH-54B are in vitro-derived subclones of a SCLC cell line, while the GLC tumours were established as cell lines from a patient during longitudinal follow-up. Both tumours were later transferred into nude mice. CPH-54A was more sensitive to single-dose irradiation than CPH-54B, while, with respect to the 3 GLC tumours examined, GLC-16 was most sensitive, followed by GLC-14 and GLC-19. The CPH tumours expressed similar amounts of c-myc and c-raf-1 mRNA, and neither expressed N-myc or L-myc. GLC-14 expressed N-myc and c-raf-1 mRNA but no c-myc. GLC-16 and GLC-19 expressed identical amounts of c-raf-1 and high levels of c-myc mRNA, but neither expressed N-myc or L-myc. None of the tumours was mutated at codon 12 or K-ras. Our results show that SCLC xenografts with different radiosensitivity may express identical amounts of some of the proto-oncogenes reported to modulate radiosensitivity. Thus, factors other than activation of the examined proto-oncogenes must be involved in causing the differences in radiosensitivity found in the SCLC xenografts. Possible long-term effects of irradiation on proto-oncogene expression was examined in xenografts of GLC-16, following regrowth after single-dose irradiation. No long-term difference in expression of c-raf-1 or c-myc mRNA was detected between control tumours and tumours irradiated with 5 or 10 Gy.
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14 MeSH Terms