| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Tumor Biology |
Department of Surgery and Interdisciplinary Oncology Program, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 33612
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
65,000 deaths each year (1)
, often as a result of metastatic liver tumors. Although numerous events leading to metastasis, such as adhesion, migration, invasion, angiogenesis, and growth, have been identified, the mechanism underlying these processes is still poorly understood. Src has been implicated in the development and progression of human colon cancer and has been the subject of numerous studies (2, 3, 4, 5, 6, 7)
. Nearly all colon carcinomas display an increased level of Src kinase activity (6
, 8)
. Src protein levels are modestly increased in adenomatous polyps and increase further during the progression of colon cancer and the development of metastatic disease (8, 9, 10, 11)
. More importantly, dramatic increases in the Src protein kinase activity during the progression of colon cancer have been observed (7)
. Studies have shown that the increase in Src activity is greater in liver metastases secondary to colorectal cancer than in those from primary tumors of other origins (12)
. Whether this increased Src activity is an event that caused the metastasis or whether it resulted from the influence of hepatic environment on the tumor is still unclear. Recently we reported an uncommon but novel mutation, termed Src-531, that occurred in 12% of human colorectal liver metastases (13)
. The mutation produces a truncated protein in which a stop codon occurs immediately COOH-terminal to the regulatory Tyr 530, eliminating the last six amino acids. The mutation is both activating and transforming when transfected into rat fibroblast cell lines, causing these cells to exhibit metastatic behavior. Presumably, in addition to increased protein levels, the increased Src activity in transfected cells is a result of the inability of the truncated Src-531 protein COOH terminus to interact with the Src homology 2 domain to inactivate the protein, maintaining a constitutively active Src protein (13)
. For these reasons, Src-531 may be used to model human colon cancer progression. Critical to the metastatic process is the release of cells from the primary tumor to foster cellular entry into the lymphovascular systems. Because increased Src activity is associated with metastasis, we hypothesized that Src activation might contribute to the process of tumor dissociation. As a measure of the potential of a primary tumor to release individual tumor cells, the degree of homotypic adhesion in cells expressing activated Src was examined using calcium-dependent dissociation assays. Src-531-transformed rodent cells or human colon cancer cell lines expressing low levels of endogenous Src but stably transfected with a mutant Src-531 construct, were used for these studies.
Proteins known to be involved in homotypic adhesion of cells include cadherins (14) , catenins, FAK3 (15) , and members of the cell cytoskeleton. Cadherins are transmembrane proteins that establish calcium-dependent homophilic protein-protein attachments between cells and are involved in embryonic morphogenesis and cell-cell adhesion in solid tissues (14 , 16, 17, 18, 19, 20) . Cadherins contain an extracellular domain, which is responsible for adhesion to similar cadherins on neighboring cells, and a cytoplasmic domain, which binds ß-catenin and creates a link to the actin cytoskeleton. It has been suggested that by using a highly activated form of v-Src, inactivation of this complex may be induced through phosphorylation of cadherins. This results in the reduction of homotypic cell-cell adhesion (21, 22) . Conversely, increased expression of active cadherins decreases invasiveness of tumor cells (23) . Hamaguchi et al. (24) also demonstrated that v-Src caused phosphorylation of N-cadherin and its associated catenins, suppressing homotypic adhesion between cells. Likewise, Behrens et al. (25) showed that phosphorylation of E-cadherins and the associated ß-catenin by v-Src caused a decrease in homotypic adhesion and an increase in invasive properties of the cells. Despite these compelling results using the highly activated v-Src, this relationship has not been explored using other forms of less-activated Src associated with human tumorigenesis. For this reason, we hypothesized that Src-531, a naturally occurring mutant form of human c-Src with modest Src activity, would provide a better model for studying this problem. Moreover, we propose that Src activation will induce a reduction of homotypic adhesion in human colon cancer cells, a process critical to the development of metastatic potential.
To assess the potential role for cadherins and catenins in Src-mediated metastasis, transfected cells were assayed to determine their adhesive characteristics via a calcium-dependent mechanism. Transfected cells were examined in an intercellular adhesion assay in the presence of Src inhibition to determine their capacity to maintain homotypic adhesions both in the presence and absence of calcium. Cells were transiently transfected with a DN Src construct to inhibit Src activity in an attempt to return cells to the wild-type adhesion phenotype and to demonstrate that altered homotypic adhesion was a specific effect of Src activity. The nature of the influence on the cadherin/catenin complex was also examined. Because v-Src is known to induce phosphorylation of the cadherin/catenin complex, causing dissociation of this complex with resulting decrease in homotypic adhesion, we explored the possibility that Src-531 would elicit a similar response. Finally, the possible roles of Ras, FAK, and STAT 3, on homotypic adhesion were examined in dissociation assays. Each of these proteins is know to be regulated, at least in part, by Src (26, 27, 28, 29) , and, thus, may be downstream components in the pathway through which Src regulates adhesion. The activity of each of these proteins was examined in an attempt to elucidate pathways through which Src mediates homotypic adhesion, which may enhance metastatic potential of cancer cells.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Western Blotting.
Proteins were isolated from cells using RIPA buffer [50 mM Tris (pH 7.5), 150 mM NaCl, 1% deoxycholate, 1% NP40, 2 mM sodium vanadate, 10 µg/ml each aprotinin and leupeptin, and 1 mM phenylmethylsulfonyl fluoride] were quantified using the Bradford assay. Fifty µg of protein were subjected to SDS-PAGE, transferred to nitrocellulose, and probed with either anti-Src or antiphosphotyrosine monoclonal antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA). Membranes were washed and probed with antimouse secondary antibody (Amersham Biosciences, Piscataway, NJ) that was conjugated with horseradish peroxidase, washed, and developed with ECL (Amersham). Tris-buffered saline-Tween was used for all washes. Results were analyzed using a Hewlett Packard laser scanner and Deskscan and Adobe Photoshop software. For immunoprecipitation, 500 µg of protein from cell extracts was incubated overnight in mouse anti-N-cadherin (Zymed Laboratories, South San Francisco, CA) antibody with protein G agarose (Life Technologies, Inc.). The beads were pelleted and washed five times in RIPA buffer. The proteins were then separated by SDS-PAGE on a 10% polyacrylamide gel, transferred to a nitrocellulose membrane with a semidry blotting apparatus (Bio-Rad), and probed as above with antiphosphotyrosine antibody (Santa Cruz).
Dissociation Assay.
Cells were seeded equally and grown to confluence. Cells were trypsinized in 0.1% trypsin containing either 1 mM EDTA (TE) or 1 mM CaCl2 (TC) and incubated at 37°C for 30 min. Cells were pipetted five times gently in 10 ml of PBS and counted in a Coulter counter. Each sample was done in triplicate. The degree of adhesion was expressed as the ratio NTC:NTE.
Fluorescence Microscopy.
Wild-type SW 480 cells and SW480 cells transfected with c-Src and Src-531 were grown to 30% confluence on tissue culture treated slides. The slides were fixed in 4% paraformaldehyde and washed in PBS. Cells were incubated with 1:100 dilution of mouse anti-N-cadherin (Zymed Laboratories) and rabbit anti-ß-catenin for 1 h at room temperature. Slides were washed in PBS and incubated with antimouse FITC-conjugated and antirabbit TRITC-conjugated secondary antibodies. 4',6diamidino-2-phenylindole (DAPI) antifade was added and slides were viewed using the Vysis system.
Src Kinase Assay.
Cells were lysed in RIPA buffer as above and protein concentration quantified. Protein (50 µg) was incubated 2 h with 2 µl (20 µg) of Src monoclonal antibody (Upstate Biotechnologies). Protein A agarose (40 µl) was added, and incubation continued an additional 2 h. Immunoprecipitated proteins were washed three times in lysis buffer and one time in kinase buffer (0.1 M HEPES, 0.02 M MgCl2, 0.01 M MnCl2, and 0.02 M DTT). The proteins were incubated with 12 µl of kinase reaction mixture containing kinase buffer, 2 µg of acid denatured enolase (Sigma-Aldrich, St. Louis, MO), 10 µM cold ATP, and 2 µCi [
-32P]ATP (NEN). The reaction was incubated at 30°C for 30 min. 20 µl of loading dye were added, the reaction was heated to 95°C for 3 min, and the proteins were separated on a 10% polyacrylamide gel. The gel was dried and exposed to Kodak X-OMAT AR film for 30 min. The films were scanned on Microtek ScanMaker.
Flow Cytometry.
Cells were grown to 90% confluence and removed from plates using Cellstripper (Mediatech) to preserve surface adhesion molecules. Cells were washed and resuspended in FACS buffer (0.1% sodium azide and 1% BSA in PBS) and incubated for 30 min with mouse monoclonal N-cadherin (Zymed Laboratories) and 30 min with antimouse secondary antibody conjugated to FITC (Zymed Laboratories). Analysis was done on FACScan (Becton Dickinson).
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. Kinase assays support these data; mock transfectants display very little basal, endogenous Src kinase activity in comparison with Src 531-transfected cell lines, which show a high level of kinase activity with the exogenous substrate enolase (Fig. 2a)
relative to Src protein levels (Fig. 2b)
. Several clones of Src-531-transfected cells were examined to eliminate the possibility of clonal artifact. In every case, cells expressing Src 531 displayed an increased level of kinase activity over cells transfected with empty vector, yet less activity than cells expressing v-Src. (data not shown).
|
|
. The addition of calcium restores homotypic adhesion in a dose-dependent manner but is less effective in Src-531-expressing cells (Fig. 3b)
. To determine whether Src-specific inhibition would result in a restoration of normal levels of homotypic adhesion, cells that express Src-531 and show reduced adhesion, were transiently transfected with a plasmid containing a DN Src clone. Fig. 4a
shows that the DN Src increases the adhesion properties of cells in a dose-dependent manner using 0.5 µg/ml and 1.0 µg/ml. DN Src at 1.0 µg/ml reduces Src protein kinase activity by 2- to 3-fold in Src 531-transfected cells (Fig. 4b)
. Similarly, incubation of cells with the Src-specific inhibitor, PD180970 (125 nM), yields similar results: increased homotypic adhesion concordant with the inhibition of Src activity (Fig. 5a)
.
|
|
|
. Ras inhibition by the DN construct resulted in increased homotypic adhesion at levels similar to the DN Src and PD180970 inhibitor, which suggested that Src may exert regulatory effects on adhesion through Ras. The possible involvement of both FAK and STAT 3ß in homotypic adhesion was also explored because both molecules are known substrates of v-Src. Moreover, both molecules are thought to play significant roles in oncogenesis and tumor progression. Dissociation assays were performed on cells stably transfected with either Src-531 or an empty vector, and transiently transfected with DN FAK (1.0 µg/ml) or STAT 3ß (1.0 µg/ml). Transfection with DN FAK results in a reduced adhesion at levels similar to those elicited by DN Src and DN Ras, which indicates that FAK may also be involved in Src-mediated homotypic adhesion. On the other hand, STAT 3ß seems to have very little effect on adhesion and serves as a reasonable control for these experiments.
Src Activity Causes Dissociation of the Cadherin/Catenin Complex.
We explored the possibility that the reduction in cell-cell adhesion is a result of alteration in the cadherin/catenin complex known to be operational in homotypic adhesion (18
, 24)
. Previous reports have suggested a role for v-Src in dissociating this complex. Fluorescence microscopy revealed a partial colocalization of N-cadherin and ß-catenin in wild-type SW480 cells at the junctions between cells as well as in the nucleus. On the other hand, Src-531 transfectants show ß-catenin located primarily in the nucleus (Fig. 6)
, with very little detected at the cell surface in a complex with N-cadherin. Wild-type SW480 cells have a partial localization of ß-catenin in the nucleus as a result of an adenomatous polyposis coli mutation in this cell line that inhibits ß-catenin degradation. Additional experiments involving immunoprecipitation of SW480 cell extracts with cadherin antibodies (Zymed) followed by Western blotting of the blots by anti-ß-catenin antibody reveals that ß-catenin coprecipitates with cadherin in wild-type cells, but very little ß-catenin is associated with cadherin in Src-531-expressing cells (Fig. 7a)
. These results are consistent with the observations in Fig. 6
that cadherin and ß-catenin appear to be minimally colocalized in Src-531 expressing cells. Western blotting of total cell lysates indicates that the levels of catenin and cadherin are similar in each cell transfectant, eliminating the possibility of altered catenin or cadherin levels causing lower association with cadherin. Flow cytometry was performed on both wild-type and Src-531-transfected SW480 cells labeled with N-cadherin. Results show that N-cadherin is present on the surface of wild-type cells, however, Src-531 expressing cells do not show surface N-cadherin. Immunofluorescence data provides a possible explanation for this occurrence. Whereas the N-cadherin staining occurs on the surface only of every wild-type cell in the sample, the Src-531 expressing cells show significant amounts of N-cadherin in the cytoplasm, and, furthermore, not every cell expresses surface N-cadherin. These data suggest that the increased Src activity from an activated mutant Src-531 is able to disrupt the cadherin/catenin complex and that the disruption of this complex may be responsible for the decrease in calcium-dependent homotypic adhesion. In addition, Src activity may be responsible for the translocation of N-cadherin to the cytoplasm, further reducing its ability to perform the role of an intercellular adhesion molecule.
|
|
. The same experiments were performed on HCT116 cells to examine the phosphorylation state of E-cadherin expressed in these cells (Fig. 7e)
. Western blotting was performed on supernatants from immunoprecipitated samples to assure that immunoprecipitated proteins were fully precipitated and not discarded with the supernatant in both kinase assays and cadherin/catenin complex assays (data not shown). |
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
In this study, the effects of activated mutant Src on the adhesive properties of human cancer cells were examined in an effort to identify a mechanism by which increased Src activity enhances the metastatic phenotype of human colon cancer cells. We hypothesized that Src expression and/or Src activation may lead to decreased intercellular adhesion, which would permit a primary tumor to release metastatic tumor cells. The SW 480 cell line was chosen because it has a low level of endogenous Src expression and activity and a normal ß-catenin, and it is known to be poorly metastatic. Src-531 was used as a natural model of Src activation. SW480 cells express N-cadherin, whereas HCT116 cells express E-cadherin. These two cell lines were used with the activated Src protein to determine whether the data represent a common phenomenon that will be widely applicable to human colon cancer. These data provide evidence that Src occurring naturally in colon tumors enhances the metastatic phenotype through reduced adhesion. Other forms of activated Src, including v-Src and the chicken Src-527, are not known to occur naturally in mammalian systems, and, therefore, may be less relevant to the human situation. Moreover, v-Src produces very high levels of Src activity that are often toxic to cells and make stable transfection difficult. These data provide evidence that Src protein occurring naturally in human tumors enhances metastatic potential by reducing homotypic adhesion of tumor cells.
Recently, Owens et al. (32) reported that c-Src family kinase activity is required for the disruption of cadherin-dependent homotypic adhesion in vitro, a finding that supports our hypothesis. On the other hand, Takeda et al. (33) provided evidence that, although v-Src activity causes ß-catenin phosphorylation to increase as cadherin-mediated adhesion is disrupted, ß-catenin phosphorylation is not necessary and, furthermore, is not involved in this disruption. Taken together, these data implicate the presence of yet another factor in the homotypic adhesion process, perhaps p-120 Cas, vinculin, integrins, or other junction proteins. These issues may need to be addressed to obtain a clear understanding of the role of Src in cell-cell adhesion.
ß-catenin plays a dual role in the structure and function of cells. It functions both in cell adhesion as a link between cell surface cadherin molecules and the actin cytoskeleton and as a signaling molecule for gene transcription (34) . On stimulation by Wnt [vertibrate homologue of the molecule wingless (Wg) an extracellular glycoprotein important in regulating cell growth and differentiation], ß-catenin is translocated to the nucleus, in which it binds to lymphoid-enhancing factor/T-cell factor transcription factors that control the transcription of genes involved in cell proliferation (35 , 36) . Inappropriate activation of this pathway can lead to the development of various tumors, as is the case with colon cancer mediated by an APC mutation (37) . Localization of catenin to the nucleus is reduced by the binding of catenins to molecules in the cytoplasm such as cadherins (36) and platelet-endothelial cell adhesion molecules (38) . Therefore, participation of ß-catenin in a cadherin/catenin complex counteracts the ability of ß-catenin to function as a transcription regulator as it enables homotypic adhesion.
Results from immunofluorescent assays and immunoprecipitation experiments indicated that the cadherin/catenin complex is disrupted in cells expressing Src-531. N-cadherin also appears to be partially translocated into the cytoplasmic region of the cell. Brabletz et al. (39) reported that E-cadherin expressed by SW480 cells appears in the cytoplasm and localizes to the membrane after 3–4 days growing in culture. N-cadherin in mock-transfected cells appears to be localized in the membrane after 3–4 days in culture. However, in Src-531-transfected cells, a pool of N-cadherin appears in the cytoplasm under identical growth conditions, rendering it incapable of performing a role as an intercellular adhesion molecule. Western blot results demonstrated that the disruption of the cadherin/catenin complex is not a result of a lack of either catenin or cadherin expression. Phosphotyrosine Western blots of immunoprecipitated proteins indicated that the dissociation of the complex may have been a result of the phosphorylation of N-cadherin in SW480 cells and of E-cadherin in HCT116 cells. Cell extracts were immunoprecipitated with ß-catenin antibodies, and Western blots were performed. The membranes were probed with phosphotyrosine and yielded no bands, indicating that ß-catenin is not phosphorylated in these cells. This may be a result of the fact that, once phosphorylated in a Src-regulated pathway, ß-catenin is targeted to the ubiquitin-mediated degradation pathway (40) . Multiple cell lines were examined to ensure that phenotypic changes in cells were the result of altered Src expression and not merely limited to a specific cell line. In every case, the mutant Src-531 stimulated a reduction in adhesion. Adhesion studies were performed under the influence of DN Src, a kinase-inactive Src protein that appears to compete with active Src for substrate binding. The DN Src restored adhesion characteristics in a dose-dependent manner, which indicated that the Src activity is responsible for decreased adhesion. Ras is known to be a downstream element in v-Src transformation and may, therefore, play a role in Src-mediated adhesion properties of cells (26 , 41) . This hypothesis was tested using the DN H-Ras (N-17). Data showing that the inhibition of Ras function in Src-transfected cells increases adhesion indicated that Ras is a downstream target for Src involvement in the pathway regulating homotypic adhesion. Src is also involved in the regulation of FAK, a molecule associated with integrins in the adhesion process. The FAK pathway may play an additional role in determining Src-mediated cell adhesion, independent of the cadherin/catenin pathway.
Collectively, these data suggest that activated Src expression may be a critical factor in the release of viable cells from the primary tumor as an initial step in metastasis. This process is linked to the disruption of the catenin/cadherin complex as a result of cadherin phosphorylation and is mediated through both Ras and FAK pathways.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 This work was supported by American Cancer Society Grants PF-99-058-01 (to R. I.) and RPG-99-099-01 (to T. Y.). 
2 To whom requests for reprints should be addressed, at Department of Surgery and Interdisciplinary Oncology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612. Phone: (813) 903-6808; E-mail: irbyr{at}moffitt.usf.edu
3 The abbreviations used are: FAK, focal adhesion kinase; v-SRC, avian Src; DN, dominant negative; RIPA, radioimmunoprecipitation assay (buffer); TRITC, tetramethylrhodamine isothiocyanate; STAT, signal transducer and activator of transcription.
Received 11/19/01. Accepted 3/ 1/02.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
catenin fusion molecules. J. Cell Biol., 127: 235-245, 1994.This article has been cited by other articles:
|
|
 |
|
  S. Van Schaeybroeck, D. M. Kelly, J. Kyula, S. Stokesberry, D. A. Fennell, P. G. Johnston, and D. B. Longley Src and ADAM-17-Mediated Shedding of Transforming Growth Factor-{alpha} Is a Mechanism of Acute Resistance to TRAIL Cancer Res., October 15, 2008; 68(20): 8312 - 8321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bedel, A. Negre-Salvayre, S. Heeneman, M.-H. Grazide, J.-C. Thiers, R. Salvayre, and F. Maupas-Schwalm E-Cadherin/{beta}-Catenin/T-Cell Factor Pathway Is Involved in Smooth Muscle Cell Proliferation Elicited by Oxidized Low-Density Lipoprotein Circ. Res., September 26, 2008; 103(7): 694 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. Kunte, R. K. Wali, J. L. Koetsier, and H. K. Roy Antiproliferative effect of sulindac in colonic neoplasia prevention: role of COOH-terminal Src kinase Mol. Cancer Ther., July 1, 2008; 7(7): 1797 - 1806. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Matteucci, E. Ridolfi, P. Maroni, P. Bendinelli, and M. A. Desiderio c-Src/Histone Deacetylase 3 Interaction Is Crucial for Hepatocyte Growth Factor Dependent Decrease of CXCR4 Expression in Highly Invasive Breast Tumor Cells Mol. Cancer Res., August 1, 2007; 5(8): 833 - 845. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Symowicz, B. P. Adley, K. J. Gleason, J. J. Johnson, S. Ghosh, D. A. Fishman, L. G. Hudson, and M. S. Stack Engagement of Collagen-Binding Integrins Promotes Matrix Metalloproteinase-9-Dependent E-Cadherin Ectodomain Shedding in Ovarian Carcinoma Cells Cancer Res., March 1, 2007; 67(5): 2030 - 2039. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Lorch, T. O. Thomas, and H.-J. Schmoll Bortezomib Inhibits Cell-Cell Adhesion and Cell Migration and Enhances Epidermal Growth Factor Receptor Inhibitor-Induced Cell Death in Squamous Cell Cancer Cancer Res., January 15, 2007; 67(2): 727 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Khare, C. Holgren, and A. M. Samarel Deoxycholic acid differentially regulates focal adhesion kinase phosphorylation: role of tyrosine phosphatase ShP2 Am J Physiol Gastrointest Liver Physiol, December 1, 2006; 291(6): G1100 - G1112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hiscox, L Morgan, T. Green, and R. I Nicholson Src as a therapeutic target in anti-hormone/anti-growth factor-resistant breast cancer Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S53 - S59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Wang, R. Lu, J. Zhao, and L. E. Limbird Arrestin Serves as a Molecular Switch, Linking Endogenous {alpha}2-Adrenergic Receptor to SRC-dependent, but Not SRC-independent, ERK Activation J. Biol. Chem., September 8, 2006; 281(36): 25948 - 25955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Koenig, C. Mueller, C. Hasel, G. Adler, and A. Menke Collagen Type I Induces Disruption of E-Cadherin-Mediated Cell-Cell Contacts and Promotes Proliferation of Pancreatic Carcinoma Cells. Cancer Res., May 1, 2006; 66(9): 4662 - 4671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. Delfino, H. Stevenson, and T. E. Smithgall A Growth-suppressive Function for the c-Fes Protein-Tyrosine Kinase in Colorectal Cancer J. Biol. Chem., March 31, 2006; 281(13): 8829 - 8835. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Qi, J. Wang, O. Romanyuk, and C.-H. Siu Involvement of Src Family Kinases in N-Cadherin Phosphorylation and beta-Catenin Dissociation during Transendothelial Migration of Melanoma Cells Mol. Biol. Cell, March 1, 2006; 17(3): 1261 - 1272. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Rao, N. Kremenevskaja, R. von Wasielewski, V. Jakubcakova, S. Kant, J. Resch, and G. Brabant Wnt/{beta}-Catenin Signaling Mediates Antineoplastic Effects of Imatinib Mesylate (Gleevec) in Anaplastic Thyroid Cancer J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 159 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Miotti, A. Tomassetti, I. Facetti, E. Sanna, V. Berno, and S. Canevari Simultaneous Expression of Caveolin-1 and E-Cadherin in Ovarian Carcinoma Cells Stabilizes Adherens Junctions through Inhibition of src-Related Kinases Am. J. Pathol., November 1, 2005; 167(5): 1411 - 1427. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Qi, N. Chen, J. Wang, and C.-H. Siu Transendothelial Migration of Melanoma Cells Involves N-Cadherin-mediated Adhesion and Activation of the {beta}-Catenin Signaling Pathway Mol. Biol. Cell, September 1, 2005; 16(9): 4386 - 4397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Torres-Roca, S. Eschrich, H. Zhao, G. Bloom, J. Sung, S. McCarthy, A. B. Cantor, A. Scuto, C. Li, S. Zhang, et al. Prediction of Radiation Sensitivity Using a Gene Expression Classifier Cancer Res., August 15, 2005; 65(16): 7169 - 7176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Ducker, J. J. Upson, K. J. French, and C. D. Smith Two N-Myristoyltransferase Isozymes Play Unique Roles in Protein Myristoylation, Proliferation, and Apoptosis Mol. Cancer Res., August 1, 2005; 3(8): 463 - 476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Golas, J. Lucas, C. Etienne, J. Golas, C. Discafani, L. Sridharan, E. Boghaert, K. Arndt, F. Ye, D. H. Boschelli, et al. SKI-606, a Src/Abl Inhibitor with In vivo Activity in Colon Tumor Xenograft Models Cancer Res., June 15, 2005; 65(12): 5358 - 5364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B.-C. Lee, T.-H. Lee, R. Zagozdzon, S. Avraham, A. Usheva, and H. K. Avraham Carboxyl-Terminal Src Kinase Homologous Kinase Negatively Regulates the Chemokine Receptor CXCR4 through YY1 and Impairs CXCR4/CXCL12 (SDF-1{alpha})-Mediated Breast Cancer Cell Migration Cancer Res., April 1, 2005; 65(7): 2840 - 2845. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. Irby, R. L. Malek, G. Bloom, J. Tsai, N. Letwin, B. C. Frank, K. Verratti, T. J. Yeatman, and N. H. Lee Iterative Microarray and RNA Interference-Based Interrogation of the Src-Induced Invasive Phenotype Cancer Res., March 1, 2005; 65(5): 1814 - 1821. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Moran, A. M. Carothers, M. J. Weyant, M. Redston, and M. M. Bertagnolli Carnosol Inhibits {beta}-Catenin Tyrosine Phosphorylation and Prevents Adenoma Formation in the C57BL/6J/Min/+ (Min/+) Mouse Cancer Res., February 1, 2005; 65(3): 1097 - 1104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Palacios, J. S. Tushir, Y. Fujita, and C. D'Souza-Schorey Lysosomal Targeting of E-Cadherin: a Unique Mechanism for the Down-Regulation of Cell-Cell Adhesion during Epithelial to Mesenchymal Transitions Mol. Cell. Biol., January 1, 2005; 25(1): 389 - 402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. F. Calvisi, S. Ladu, V. M. Factor, and S. S. Thorgeirsson Activation of {beta}-catenin provides proliferative and invasive advantages in c-myc/TGF-{alpha} hepatocarcinogenesis promoted by phenobarbital Carcinogenesis, June 1, 2004; 25(6): 901 - 908. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. LIU and D. R. SENGER Matrix-specific activation of Src and Rho initiates capillary morphogenesis of endothelial cells FASEB J, March 1, 2004; 18(3): 457 - 468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Frame Newest findings on the oldest oncogene; how activated src does it J. Cell Sci., March 1, 2004; 117(7): 989 - 998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-B. Guo, I. Lee, M. Kamar, and M. Pierce N-Acetylglucosaminyltransferase V Expression Levels Regulate Cadherin-associated Homotypic Cell-Cell Adhesion and Intracellular Signaling Pathways J. Biol. Chem., December 26, 2003; 278(52): 52412 - 52424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sun, L. Yang, R. I. Feldman, X.-m. Sun, K. N. Bhalla, R. Jove, S. V. Nicosia, and J. Q. Cheng Activation of Phosphatidylinositol 3-Kinase/Akt Pathway by Androgen through Interaction of p85{alpha}, Androgen Receptor, and Src J. Biol. Chem., October 31, 2003; 278(44): 42992 - 43000. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
