Bio

Clinical Focus


  • Inflammatory Bowel Diseases
  • Gastroenterology

Administrative Appointments


  • Director, Program for Inflammatory Bowel Diseases, Stanford University School of Medicine (1989 - Present)

Honors & Awards


  • Outstanding AGA Women in Science, American Gastroenterological Association (2008)
  • Premier Physician Award, Crohn's & Colitis Foundation of America - Greater Bay Area Chapter (2000)
  • Member, American Society for Clinical Investigation (1995)

Professional Education


  • BS, Stanford University, Biology (1973)
  • MD, University of Utah, Medicine (1978)
  • Internship:UCSD Medical Center (1979) CA
  • Residency:UCSD Medical Center (1981) CA
  • Fellowship:UCSD Medical Center (1984) CA
  • Research Associate, The Salk Institute, Cancer Biology (1989)
  • Board Certification: Internal Medicine, American Board of Internal Medicine (1981)
  • Board Certification: Gastroenterology, American Board of Internal Medicine (1987)
  • Medical Education:University of Utah School of Medicine (1978) UT

Community and International Work


  • Inflammatory Bowel Diseases

    Topic

    Clinical Care and Education

    Partnering Organization(s)

    Crohn's and Colitis Foundation of America

    Populations Served

    Northern California

    Location

    Bay Area

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

Research & Scholarship

Current Research and Scholarly Interests


Research in my laboratory focuses on molecular mechanisms of intestinal cell growth control. A primary focus is on function and regulation of the Src family of tyrosine kinases in normal cells, and their deregulation in cancer cells. Molecular, cellular and physiologic approaches are used to explore basic questions about growth regulation. Areas of active investigation include studies of Src function in cell cycle progression, proliferation, differentiation, adhesion, survival and malignant transformation; discovery of endogenous inhibitors of Src kinases; analysis of inhibitor function in cell growth control and apoptosis; and exploration of new drug therapy for colon cancer. Our recent discovery of a Src inhibitor, RACK1, which works both to inhibit growth (by suppressing Src activity at G1 and mitotic checkpoints) and to induce death of colon cells, could be exploited for development of new and more powerful and selective strategies for treatment of human colon cancer.

Teaching

2013-14 Courses


Graduate and Fellowship Programs


Publications

Journal Articles


  • Rack1 promotes epithelial cell-cell adhesion by regulating E-cadherin endocytosis ONCOGENE Swaminathan, G., Cartwright, C. A. 2012; 31 (3): 376-389

    Abstract

    E-cadherin and its cytoplasmic partners, catenins, mediate epithelial cell-cell adhesion. Disruption of this adhesion allows cancer cells to invade and metastasize. Aberrant activation of the Src tyrosine kinase disrupts cell-cell contacts through an E-cadherin/catenin-dependent mechanism. Previously we showed that Rack1 regulates the growth of colon cells by suppressing Src activity at G(1) and mitotic checkpoints, and in the intrinsic apoptotic and Akt cell survival pathways. Here we show that Rack1, partly by inhibiting Src, promotes cell-cell adhesion and reduces the invasive potential of colon cancer cells. Rack1 stabilizes E-cadherin and catenins at cell-cell contacts by inhibiting the Src phosphorylation of E-cadherin, the ubiquitination of E-cadherin by the E3 ligase Hakai and the endocytosis of E-cadherin. Upon depletion and restoration of extracellular calcium, Rack1 facilitates the re-assembly of E-cadherin-containing cell-cell contacts. Rack1 also blocks HGF-induced endocytosis of E-cadherin, disruption of cell-cell contacts and cell scatter. Our results uncover a novel function of Rack1 in maintaining the junctional homeostasis of intestinal epithelial cells by regulation of the Src- and growth factor-induced endocytosis of E-cadherin.

    View details for DOI 10.1038/onc.2011.242

    View details for Web of Science ID 000299542100010

    View details for PubMedID 21685945

  • A novel pro-apoptotic function of RACK1: suppression of Src activity in the intrinsic and Akt pathways ONCOGENE Mamidipudi, V., Cartwright, C. A. 2009; 28 (50): 4421-4433

    Abstract

    Earlier we showed that RACK1 regulates growth of human colon cells by suppressing Src activity at G(1) and mitotic checkpoints. Here, we show that RACK1 also induces apoptosis of the cells, partly by inhibiting Src. In the intrinsic pathway, RACK1 inhibits expression of anti-apoptotic Bcl-2 and Bcl-X(L), induces expression of pro-apoptotic Bim, targets Bim and Bax to the mitochondria, induces oligomerization of Bax (which requires Bim and inhibition of Src), depolarizes mitochondria membranes, releases cytochrome c, and activates caspases-9 and -3 and death substrates. Bax and Bim are required for RACK1-mediated mitochondrial cell death. RACK1-induced oligomerization of Bax is required for staurosporine-mediated cell death. RACK1 also induces apoptosis by blocking Src activation of the Akt cell survival pathway. This leads to activation of the transcription factor FOXO3, a potent inducer of apoptosis and G(1) arrest. Collectively, our results show that RACK1, partly by inhibiting Src, promotes mitochondrial cell death and blocks Akt-mediated cell survival. Thus, RACK1 inhibits growth and induces death of colon cells. Exploitation of these dual functions could lead to novel colon cancer therapies that mimic RACK1 function.

    View details for DOI 10.1038/onc.2009.293

    View details for Web of Science ID 000272876500002

    View details for PubMedID 19767770

  • Crohn's Colitis Complicated by Cytomegalovirus Infection DIGESTIVE DISEASES AND SCIENCES Levesque, B. G., Pai, R., Cartwright, C. A. 2009; 54 (9): 1864-1867

    View details for DOI 10.1007/s10620-009-0879-0

    View details for Web of Science ID 000268324000008

    View details for PubMedID 19575294

  • RACK1 inhibits colonic cell growth by regulating Src activity at cell cycle checkpoints ONCOGENE Mamidipudi, V., Dhillon, N. K., Parman, T., Miller, L. D., Lee, K. C., Cartwright, C. A. 2007; 26 (20): 2914-2924

    Abstract

    Previously, we showed that Src tyrosine kinases are activated early in the development of human colon cancer and are suppressed as intestinal cells differentiate. We identified RACK1 as an endogenous substrate, binding partner and inhibitor of Src. Here we show (by overexpressing RACK1, depleting Src or RACK1 and utilizing cell-permeable peptides that perturb RACK1's interaction with Src) that RACK1 regulates growth of colon cells by suppressing Src activity at G(1) and mitotic checkpoints, and consequently delaying cell cycle progression. Activated Src rescues RACK1-inhibited growth of HT-29 cells. Conversely, inhibiting Src abolishes growth promoted by RACK1 depletion in normal cells. Two potential mechanisms whereby RACK1 regulates mitotic exit are identified: suppression of Src-mediated Sam68 phosphorylation and maintenance of the cyclin-dependent kinase (CDK) 1-cyclin B complex in an active state. Our results reveal novel mechanisms of cell cycle control in G(1) and mitosis of colon cells. The significance of this work lies in the discovery of a mechanism by which the growth of colon cancer cells can be slowed, by RACK1 suppression of an oncogenic kinase at critical cell cycle checkpoints. Small molecules that mimic RACK1 function may provide a powerful new approach to the treatment of colon cancer.

    View details for DOI 10.1038/sj.onc.1210091

    View details for Web of Science ID 000246210800011

    View details for PubMedID 17072338

  • Peptide modulators of Src activity in G(1) regulate entry into S phase and proliferation of NIH 3T3 cells BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Mamidipudi, V., Miller, L. D., Mochly-Rosen, D., Cartwright, C. A. 2007; 352 (2): 423-430

    Abstract

    Cascades of kinases and phosphatases are regulated by selective protein-protein interactions that are essential for signal transduction. Peptide modulators of these interactions have been used to dissect the function of individual components of the signaling cascade, without relying on either the over- or underexpression of proteins. Previously, we identified RACK1 as an endogenous substrate, binding partner and inhibitor of Src tyrosine kinases. Here, we utilized cell-permeable peptides that selectively disrupt or enhance the interaction of RACK1 and Src to further examine the function of RACK1. Our results provide direct physiologic evidence that RACK1 regulates growth of NIH3T3 cells by suppressing the activity of Src and other cell cycle regulators in G1, and delaying entry into S phase. They also demonstrate the potential for using peptide modulators of Src activity as a tool for regulating cell growth, and for designing new strategies for cancer therapy that target specific protein-protein interactions.

    View details for DOI 10.1016/j.bbrc.2006.11.034

    View details for Web of Science ID 000243196300023

    View details for PubMedID 17118337

  • RACK1 regulates G(1)/S progression by suppressing Src kinase activity MOLECULAR AND CELLULAR BIOLOGY Mamidipudi, V., Zhang, J., Lee, K. C., Cartwright, C. A. 2004; 24 (15): 6788-6798

    Abstract

    Cancer genes exert their greatest influence on the cell cycle by targeting regulators of a critical checkpoint in late G(1). Once cells pass this checkpoint, they are fated to replicate DNA and divide. Cancer cells subvert controls at work at this restriction point and remain in cycle. Previously, we showed that RACK1 inhibits the oncogenic Src tyrosine kinase and NIH 3T3 cell growth. RACK1 inhibits cell growth, in part, by prolonging G(0)/G(1). Here we show that RACK1 overexpression induces a partial G(1) arrest by suppressing Src activity at the G(1) checkpoint. RACK1 works through Src to inhibit Vav2, Rho GTPases, Stat3, and Myc. Consequently, cyclin D1 and cyclin-dependent kinases 4 and 2 (CDK4 and CDK2, respectively) are suppressed, CDK inhibitor p27 and retinoblastoma protein are activated, E2F1 is sequestered, and G(1)/S progression is delayed. Conversely, downregulation of RACK1 by short interference RNA activates Src-mediated signaling, induces Myc and cyclin D1, and accelerates G(1)/S progression. RACK1 suppresses Src- but not mitogen-activated protein kinase-dependent platelet-derived growth factor signaling. We also show that Stat3 is required for Rac1 induction of Myc. Our results reveal a novel mechanism of cell cycle control in late G(1) that works via an endogenous inhibitor of the Src kinase.

    View details for DOI 10.1128/MCB.24.15.6788-6798.2004

    View details for Web of Science ID 000222764800024

    View details for PubMedID 15254245

  • RACK1 regulates Src-mediated Sam68 and p190RhoGAP signaling ONCOGENE Miller, L. D., Lee, K. C., Mochly-Rosen, D., Cartwright, C. A. 2004; 23 (33): 5682-5686

    Abstract

    RACK1 is the founding member of a family of receptors for activated C kinase collectively called RACKs. Upon activation of PKC, RACK1 co-localizes with the Src tyrosine kinase at the plasma membrane and functions as a substrate, binding partner and inhibitor of Src (as measured in vitro), and a growth inhibitor in NIH 3T3 cells. To further analyze the function of RACK1 in Src and PKC signaling, we utilized cell-permeable peptides that modulate the interaction of RACK1 and betaIIPKC, thereby affecting betaIIPKC translocation and function. We found that the association of betaIIPKC and RACK1 is necessary for Src phosphorylation of RACK1. Src activity is required for tyrosine phosphorylation of RACK1, and for RACK1 binding to Src, but not to betaIIPKC. Endogenous Src kinase activity, as measured by phosphorylation of Sam68 (a mitotic-specific Src substrate involved in cell cycle regulation and RNA splicing) or p190RhoGAP (a Src substrate and GTPase-activating protein involved in actin reorganization), increases with disruption of the Src-RACK1 complex, and decreases with enhanced complex formation. RACK1 inhibits Src-mediated p190RhoGAP signaling and actin cytoskeleton rearrangement. Thus, RACK1 functions as an endogenous inhibitor of the Src kinase in diverse signaling pathways that regulate distinct cellular functions. Our results demonstrate the potential for using peptide modulators of Src activity as a tool for uncovering the function of Src in cells.

    View details for DOI 10.1038/sj.onc.1207735

    View details for Web of Science ID 000222629500013

    View details for PubMedID 15184885

  • RACK1 inhibits the serum- and anchorage-independent growth of v-Src transformed cells FEBS LETTERS Mamidipudi, V., Chang, B. Y., Harte, R. A., Lee, K. C., Cartwright, C. A. 2004; 567 (2-3): 321-326

    Abstract

    Cancer cells are capable of serum- and anchorage-independent growth, and focus formation on monolayers of normal cells. Previously, we showed that RACK1 inhibits c-Src kinase activity and NIH3T3 cell growth. Here, we show that RACK1 partially inhibits v-Src kinase activity, and the serum- and anchorage-independent growth of v-Src transformed cells, but has no effect on focus formation. RACK1-overexpressing v-Src cells show disassembly of podosomes, which are actin-rich structures that are distinctive to fully transformed cells. Together, our results demonstrate that RACK1 overexpression in v-Src cells partially reverses the transformed phenotype of the cells. Our results identify an endogenous inhibitor of the oncogenic Src tyrosine kinase and of cell transformation.

    View details for DOI 10.1016/j.febslet.2004.03.125

    View details for Web of Science ID 000221890000031

    View details for PubMedID 15178345

  • Cytomegalovirus infection in steroid-refractory ulcerative colitis - A case-control study AMERICAN JOURNAL OF SURGICAL PATHOLOGY Kambham, N., Vij, R., Cartwright, C. A., Longacre, T. 2004; 28 (3): 365-373

    Abstract

    Cytomegalovirus (CMV) infection is reported to be a cause of steroid-refractory ulcerative colitis (UC), but the strength of this association has not been tested in a case control study. Controlled studies have also not been performed to determine the sensitivity of available immunohistochemical techniques to detect CMV in this setting. The pathology database at Stanford Hospital was searched for UC patients with a diagnosis of "severe colitis" between the years 1992 and 2002 and medical records were reviewed. Forty patients were identified with refractory UC, defined as poor response to highdose systemic steroids for >2 weeks. Another group of 40 patients with severe, but nonrefractory, UC was case-matched for age and year of biopsy. A series of 40 patients who underwent colectomy for reasons other than inflammatory bowel disease with representative sections of "normal" colon were selected as noncolitis controls. CMV inclusions were detected on hematoxylin and eosin (H&E) in 2 of 40 patients with refractory UC, but not in other patients. Immunohistochemistry (IHC) detected CMV in 10 of 40 (25%) patients with refractory UC and 1 of 40 (2.5%) patients with nonrefractory UC (P = 0.007). The CMV-positive cases initially identified on IHC but not on H&E were re-reviewed for viral inclusions on H&E: 3 had rare, but typical, inclusions; 3 had atypical inclusions; and 3 had no inclusions. CMV was not detected by H&E or IHC in 40 noncolitis controls. Of 10 steroid-refractory UC patients with CMV detected, 7 were refractory to cyclosporin or 6-mercaptopurine/azathioprine (70%) and 6 had undergone proctocolectomy (60%) prior to detection of the CMV. Two patients with recognized CMV infection were treated with gancyclovir, improved, and were able to taper off steroids and avoid proctocolectomy. This study provides evidence that unrecognized and therefore untreated CMV infection is significantly associated with steroid-refractory UC. Moreover, IHC is more sensitive than H&E for detection of CMV and should be considered as part of the routine evaluation of steroid-refractory UC patients, before proceeding with other medical or surgical therapy that may be unnecessary once the CMV is treated.

    View details for Web of Science ID 000189316500009

    View details for PubMedID 15104299

  • Detection of protein kinase-binding partners by the yeast two-hybrid analysis. Methods in molecular biology (Clifton, N.J.) Chang, B. Y., Cartwright, C. A. 2003; 233: 327-343

    View details for PubMedID 12840519

  • RACK1: a novel substrate for the Src protein-tyrosine kinase ONCOGENE Chang, B. Y., Harte, R. A., Cartwright, C. A. 2002; 21 (50): 7619-7629

    Abstract

    RACK1 is one of a group of PKC-interacting proteins collectively called RACKs (Receptors for Activated C-Kinases). Previously, we showed that RACK1 also interacts with the Src tyrosine kinase, and is an inhibitor of Src activity and cell growth. PKC activation induces the intracellular movement and co-localization of RACK1 and Src, and the tyrosine phosphorylation of RACK1. To determine whether RACK1 is a Src substrate, we assessed phosphorylation of RACK1 by various tyrosine kinases in vitro, and by kinase-active and inactive mutants of Src in vivo. We found that RACK1 is a Src substrate. Moreover, Src activity is necessary for both the tyrosine phosphorylation of RACK1 and the binding of RACK1 to Src's SH2 domain that occur following PKC activation. To identify the tyrosine(s) on RACK1 that is phosphorylated by Src, we generated and tested a series of RACK1 mutants. We found that Src phosphorylates RACK1 on Tyr 228 and/or Tyr 246, highly-conserved tyrosines located in the sixth WD repeat that interact with Src's SH2 domain. We think that RACK1 is an important Src substrate that signals downstream of growth factor receptor tyrosine kinases and is involved in the regulation of Src function and cell growth.

    View details for DOI 10.1038/sj.onc.1206002

    View details for Web of Science ID 000178756200002

    View details for PubMedID 12400005

  • The interaction of Src and RACK1 is enhanced by activation of protein kinase C and tyrosine phosphorylation of RACK1 JOURNAL OF BIOLOGICAL CHEMISTRY Chang, B. Y., Chiang, M. L., Cartwright, C. A. 2001; 276 (23): 20346-20356

    Abstract

    RACK1 is an intracellular receptor for the serine/ threonine protein kinase C. Previously, we demonstrated that RACK1 also interacts with the Src protein-tyrosine kinase. RACK1, via its association with these protein kinases, may play a key role in signal transduction. To further characterize the Src-RACK1 interaction and to analyze mechanisms by which cross-talk occurs between the two RACK1-linked signaling kinases, we identified sites on Src and RACK1 that mediate their binding, and factors that regulate their interaction. We found that the interaction of Src and RACK1 is mediated, in part, by the SH2 domain of Src and by phosphotyrosines in the sixth WD repeat of RACK1, and is enhanced by serum or platelet-derived growth factor stimulation, protein kinase C activation, and tyrosine phosphorylation of RACK1. To the best of our knowledge, this is the first report of tyrosine phosphorylation of a member of the WD repeat family of proteins. We think that tyrosine phosphorylation of these proteins is an important mechanism of signal transduction in cells.

    View details for Web of Science ID 000169135100092

    View details for PubMedID 11279199

  • The Shp-2 tyrosine phosphatase activates the Src tyrosine kinase by a non-enzymatic mechanism ONCOGENE Walter, A. O., Peng, Z. Y., Cartwright, C. A. 1999; 18 (11): 1911-1920

    Abstract

    Previously, we demonstrated that the Src tyrosine kinase interacts with the Shp-2 tyrosine phosphatase. To determine whether Shp-2 regulates Src kinase activity, we measured Src activity in cells overexpressing wild-type or catalytically-inactive C463S Shp-2. We observed a 2-3-fold increase in the specific activity of Src in both cell types and the increase did not appear to be due to dephosphorylation of Tyr 527 or phosphorylation of Tyr 416 on Src. Conversely, we observed a 2-3-fold decrease in the specific activity of Src when Shp-2 expression was inhibited. Using glutathione S-transferase-fusion proteins, we demonstrated that Shp-2 binds to the SH3 domain of Src. Our findings reveal that the Shp-2 tyrosine phosphatase can regulate the Src tyrosine kinase by a non-enzymatic mechanism. We also found that the phosphatase activity of Shp-2 immunoprecipitates is downregulated in cells transformed by Src or other proteins, and that Shp-2 preferentially associates with the membrane fraction of transformed cells. We suggest that membrane-association of Shp-2 is important for regulating Shp-2 activity.

    View details for Web of Science ID 000079191300001

    View details for PubMedID 10208413

  • RACK1, a receptor for activated C kinase and a homolog of the beta subunit of G proteins, inhibits activity of Src tyrosine kinases and growth of NIH 3T3 cells MOLECULAR AND CELLULAR BIOLOGY Chang, B. Y., Conroy, K. B., Machleder, E. M., Cartwright, C. A. 1998; 18 (6): 3245-3256

    Abstract

    To isolate and characterize proteins that interact with the unique domain and SH3 and SH2 domains of Src and potentially regulate Src activity, we used the yeast two-hybrid assay to screen a human lung fibroblast cDNA library. We identified RACK1, a receptor for activated C kinase and a homolog of the beta subunit of G proteins, as a Src-binding protein. Using GST-Src fusion proteins, we determined that RACK1 binds to the SH2 domain of Src. Coimmunoprecipitation of Src and RACK1 was demonstrated with NIH 3T3 cells. Purified GST-RACK1 inhibited the in vitro kinase activity of Src in a concentration-dependent manner. GST-RACK1 (2 microM) inhibited the activities of purified Src and Lck tyrosine kinases by 40 to 50% but did not inhibit the activities of three serine/threonine kinases that we tested. Tyrosine phosphorylation on many cellular proteins decreased in 293T cells that transiently overexpressed RACK1. Src activity and cell growth rates decreased by 40 to 50% in NIH 3T3 cells that stably overexpressed RACK1. Flow cytometric analyses revealed that RACK1-overexpressing cells do not show an increased rate of necrosis or apoptosis but do spend significantly more time in G0/G1 than do wild-type cells. Prolongation of G0/G1 could account for the increased doubling time of RACK1-overexpressing cells. We suggest that RACK1 exerts its effect on the NIH 3T3 cell cycle in part by inhibiting Src activity.

    View details for Web of Science ID 000073628800015

    View details for PubMedID 9584165

  • REGULATION OF THE SRC TYROSINE KINASE AND SYP TYROSINE PHOSPHATASE BY THEIR CELLULAR-ASSOCIATION ONCOGENE Peng, Z. Y., Cartwright, C. A. 1995; 11 (10): 1955-1962

    Abstract

    The specific activity of the Src tyrosine kinase is elevated in human colon carcinoma cells. To identify Src-binding proteins that might upregulate Src activity in these cells, a human colon carcinoma lambda gt11 expression library was screened with purified, 32P-labeled Src. The SH-PTP2 (Syp) tyrosine phosphatase was isolated and shown to associate with Src. In vitro studies demonstrated that: (1) transforming F527 Src phosphorylates Syp, and (2) Syp dephosphorylates Src at Tyr 527. Both events are known to upregulate enzyme activity. Others have shown that overexpression of the receptor tyrosine phosphatase alpha in rat embryo fibroblasts results in Src activation by dephosphorylation of Tyr 527, cell transformation and tumorigenesis. Thus, transmembrane tyrosine phosphatases may be involved in cell transformation exerting at least some of their effects through activation of Src. To the best of our knowledge, this is the first identification of an intracellular tyrosine, phosphatase which may activate Src by a similar mechanism.

    View details for Web of Science ID A1995TF29700004

    View details for PubMedID 7478513

  • SRC ACTIVITY INCREASES AND YES ACTIVITY DECREASES DURING MITOSIS OF HUMAN COLON-CARCINOMA CELLS MOLECULAR AND CELLULAR BIOLOGY Park, J., Cartwright, C. A. 1995; 15 (5): 2374-2382

    Abstract

    Src and Yes protein-tyrosine kinase activities are elevated in malignant and premalignant tumors of the colon. To determine whether Src activity is elevated throughout the human colon carcinoma cell cycle as it is in polyomavirus middle T antigen- or F527 Src-transformed cells, and whether Yes activity, which is lower than that of Src in the carcinoma cells, is regulated differently, we measured their activities in cycling cells. We observed that the activities of both kinases were higher throughout all phases of the HT-29 colon carcinoma cell cycle than in corresponding phases of the fibroblast cycle. In addition, during mitosis of HT-29 cells, Src specific activity increased two- to threefold more, while Yes activity and abundance decreased threefold. The decreased steady-state protein levels of Yes during mitosis appeared to be due to both decreased synthesis and increased degradation of the protein. Inhibition of tyrosine but not serine/threonine phosphatases abolished the mitotic activation of Src. Mitotic Src was phosphorylated at novel serine and threonine sites and dephosphorylated at Tyr-527. Two cellular proteins (p160 and p180) were phosphorylated on tyrosine only during mitosis. Tyrosine phosphorylation of several other proteins decreased during mitosis. Thus, Src in HT-29 colon carcinoma cells, similar to Src complexed to polyomavirus middle T antigen or activated by mutation at Tyr-527, is highly active in all phases of the cell cycle. Moreover, Src activity further increases during mitosis, whereas Yes activity and abundance decrease. Thus, Src and Yes appear to be regulated differently during mitosis of HT-29 colon carcinoma cells.

    View details for Web of Science ID A1995QU66500006

    View details for PubMedID 7739521

  • ELEVATED C-YES TYROSINE KINASE-ACTIVITY IN PREMALIGNANT LESIONS OF THE COLON GASTROENTEROLOGY PENA, S. V., Melhem, M. F., Meisler, A. I., Cartwright, C. A. 1995; 108 (1): 117-124

    Abstract

    The cellular oncogene c-yes and its viral homologue v-yes (the transforming gene of Yamaguchi 73 and Esh avian sarcoma viruses) encode 62-kilodalton, cytoplasmic, membrane-associated, protein-tyrosine kinases. For the related Src kinase, a close correlation exists between elevated kinase activity and cell transformation. Previously, we observed elevated Yes activity in many human colon carcinomas. Colonic neoplasia provides an opportunity to study tumor progression because most carcinomas arise from adenomas, which in turn arise from normal epithelia. The malignant potential of adenomas varies with size, histology, and degree of dysplasia. Large adenomas (> or = 2 cm) with villous architecture and severe dysplasia are most likely to develop carcinoma.To determine whether Yes is activated in premalignant lesions of the colon, we measured its in vitro protein-tyrosine kinase activity in 21 colonic adenomas from 17 patients.Activity of Yes in adenomas at greatest risk for cancer was significantly greater (12- or 14-fold as measured by enolase or autophosphorylation, respectively) than activity in adjacent normal mucosa. Moreover, villous structure, large size (> or = 2 cm), or severe dysplasia correlated with elevated Yes activity.The activity of Yes is elevated in adenomas that are at greatest risk for developing cancer.

    View details for Web of Science ID A1995PZ13500014

    View details for PubMedID 7806032

  • ELEVATED C-SRC TYROSINE KINASE-ACTIVITY IN PREMALIGNANT EPITHELIA OF ULCERATIVE-COLITIS JOURNAL OF CLINICAL INVESTIGATION Cartwright, C. A., COAD, C. A., Egbert, B. M. 1994; 93 (2): 509-515

    Abstract

    Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a high incidence of colon cancer. Dysplasia is a precursor to carcinoma and a predictor of malignant potential; epithelia containing high-grade or severe dysplasia is most likely to develop cancer. The cellular oncogene c-src and its viral homologue v-src (the transforming gene of Rous sarcoma virus) encode 60-kD cytoplasmic, membrane-associated protein tyrosine kinases. For the viral protein or transforming mutants of the cellular protein (Src), a close correlation exists between elevated tyrosine kinase activity and malignant transformation of cells. Previously, we and others observed elevated Src activity in sporadic colon carcinomas and benign adenomas at greatest risk for developing cancer (those with large size, villous architecture, and/or severe dysplasia). Here we report that Src activity and protein abundance are also elevated in neoplastic UC epithelia. Activity is highest in malignant and severely dysplastic epithelia, and 6-10-fold higher in mildly dysplastic than in nondysplastic epithelia. Thus, Src activity is elevated in premalignant UC epithelia, which is at greatest risk for developing cancer. The data suggest that activation of the src proto-oncogene is an early event in the genesis of UC colon cancer.

    View details for Web of Science ID A1994MY29600011

    View details for PubMedID 7509341

  • C-YES TYROSINE KINASE-ACTIVITY IN HUMAN COLON-CARCINOMA ONCOGENE Park, J. S., Meisler, A. I., Cartwright, C. A. 1993; 8 (10): 2627-2635

    Abstract

    To examine the role of Src-related proteins in human colon carcinoma we measured the tyrosine kinase activity of pp60c-src (Src), p62c-yes (Yes), p56lck (Lck), p59fyn (Fyn), p59hck (Hck), p56lyn (Lyn) and p55c-fgr (Fgr) from colonic cells. Yes activity, similar to that of Src, was 10-20 fold higher in three of five colon carcinoma cell lines and fivefold higher in 10 of 21 primary colon cancers than that in normal colonic cells. Lck activity was present in COLO 205 cells, otherwise Lck, Fyn, Hck, Lyn and Fgr activities were not detected in any of the carcinoma cell lines or cancers tested. Increased Yes activity, like that of Src, was due mostly to increased protein levels and not to an apparent decrease in phosphorylation of Tyr 537, the major mechanisms known to deregulate enzymatic activity. Only those colon carcinoma cell lines with elevated Src and/or Yes tyrosine kinase activity as measured in vitro had elevated levels of three tyrosine-phosphorylated proteins as measured in vivo. Thus, colon carcinoma cells contain active tyrosine kinases and/or inactive tyrosine phosphatases not present in normal colonic cells, and Src and Yes appear to be active kinases in the carcinoma cells. These data, together with those demonstrating decreased Src activity in fully differentiated enterocytes, suggest that down regulation of Src-related tyrosine kinases is important for differentiation, and/or deregulation of the kinases is important for growth and transformation of intestinal epithelial cells.

    View details for Web of Science ID A1993LX34300003

    View details for PubMedID 7690925

  • INTESTINAL CRYPT CELLS CONTAIN HIGHER LEVELS OF CYTOSKELETAL-ASSOCIATED PP60C-SRC PROTEIN TYROSINE KINASE-ACTIVITY THAN DO DIFFERENTIATED ENTEROCYTES ONCOGENE Cartwright, C. A., MAMAJIWALLA, S., SKOLNICK, S. A., Eckhart, W., Burgess, D. R. 1993; 8 (4): 1033-1039

    Abstract

    Undifferentiated crypt cells from chicken small intestine contain 15-fold higher levels of tyrosine-phosphorylated proteins than do differentiated enterocytes located at the villus apex. The tyrosine kinase activity and the tyrosine-phosphorylated proteins are associated with the Triton-insoluble cytoskeleton. To determine whether: (1) pp60c-src is an active tyrosine kinase in crypt cell cytoskeletons and (2) cytoskeletal-associated pp60c-src activity decreases as crypt cells differentiate, we isolated pp60c-src from subcellular fractions of cells along the crypt-villus axis of chicken small intestine and measured its protein kinase activity. We observed that pp60c-src activity in crypt cytoskeleton was higher (on average, fourfold as measured by enolase phosphorylation or sevenfold as measured by autophosphorylation) than that in cytoskeletons from differentiated enterocytes. Moreover, nearly 70% of pp60c-src activity in crypt cells, like that of pp60v-src, pp60c-src mutants with elevated kinase, activity or pp60v-src from activated platelets, localized to the cellular cytoskeleton. In contrast, less than 20% of pp60c-src activity in differentiated enterocytes, like that of kinase-inactive pp60v-src or pp60c-src from fibroblasts or resting platelets, associated with the cytoskeleton. Furthermore, in crypt cells, unlike differentiated enterocytes, cytoskeletal-associated pp60c-src appeared to have higher specific protein tyrosine kinase activity than did soluble pp60c-src. The data suggest that a kinase-active form of pp60c-src located in the cytoskeleton of crypt cells may be responsible for phosphorylating proteins on tyrosine and regulating growth and differentiation of the cells.

    View details for Web of Science ID A1993KT22000027

    View details for PubMedID 7681158

  • THE HEPATITIS-B VIRUS-ENCODED TRANSCRIPTIONAL TRANSACTIVATOR HBX APPEARS TO BE A NOVEL PROTEIN SERINE THREONINE KINASE CELL Wu, J. Y., Zhou, Z. Y., Judd, A., Cartwright, C. A., Robinson, W. S. 1990; 63 (4): 687-695

    Abstract

    To study the functional mechanism of the hepatitis B virus (HBV) X (hbx) gene product, we have expressed the hbx protein in E. coli and purified it by HPLC. The purified hbx protein was shown to be active in transactivating transcription directed by the LTR sequence of HIV-1. The hbx protein was found to have an intrinsic serine/threonine protein kinase activity. The hbx protein was detected in hepatitis B virions, and tryptic phosphopeptide maps of the hbx protein phosphorylated in the virion and of the in vitro phosphorylated bacterially expressed hbx protein were similar. Inactivation of the hbx protein by heat, protein-denaturing agents, or an ATP affinity analog, p-fluorosulfonylbenzoyl 5'-adenosine, resulted in loss of both protein kinase activity and trans-activation activity. These results suggest that the HBV-encoded trans-activator hbx is a novel protein kinase.

    View details for Web of Science ID A1990EJ59000005

    View details for PubMedID 2225072

  • Relapse of Intestinal and Hepatic Amebiasis After Treatment DIGESTIVE DISEASES AND SCIENCES Hwang, E. W., Cheung, L., Mojtahed, A., Cartwright, C. A. 2011; 56 (3): 677-680

    View details for DOI 10.1007/s10620-010-1492-y

    View details for Web of Science ID 000287501500009

    View details for PubMedID 21174149

  • Characterization of In Vivo Keratin 19 Phosphorylation on Tyrosine-391 PLOS ONE Zhou, Q., Snider, N. T., Liao, J., Li, D. H., Hong, A., Ku, N., Cartwright, C. A., Omary, M. B. 2010; 5 (10)

    Abstract

    Keratin polypeptide 19 (K19) is a type I intermediate filament protein that is expressed in stratified and simple-type epithelia. Although K19 is known to be phosphorylated on tyrosine residue(s), conclusive site-specific characterization of these residue(s) and identification potential kinases that may be involved has not been reported.In this study, biochemical, molecular and immunological approaches were undertaken in order to identify and characterize K19 tyrosine phosphorylation. Upon treatment with pervanadate, a tyrosine phosphatase inhibitor, human K19 (hK19) was phosphorylated on tyrosine 391, located in the 'tail' domain of the protein. K19 Y391 phosphorylation was confirmed using site-directed mutagenesis and cell transfection coupled with the generation of a K19 phospho (p)-Y391-specific rabbit antibody. The antibody also recognized mouse phospho-K19 (K19 pY394). This tyrosine residue is not phosphorylated under basal conditions, but becomes phosphorylated in the presence of Src kinase in vitro and in cells expressing constitutively-active Src. Pervanadate treatment in vivo resulted in phosphorylation of K19 Y394 and Y391 in colonic epithelial cells of non-transgenic mice and hK19-overexpressing mice, respectively.Human K19 tyrosine 391 is phosphorylated, potentially by Src kinase, and is the first well-defined tyrosine phosphorylation site of any keratin protein. The lack of detection of K19 pY391 in the absence of tyrosine phosphatase inhibition suggests that its phosphorylation is highly dynamic.

    View details for DOI 10.1371/journal.pone.0013538

    View details for Web of Science ID 000283422100006

    View details for PubMedID 21049038

  • Distal Extrahepatic Cholangiocarcinoma Presenting as Cholangitis DIGESTIVE DISEASES AND SCIENCES Lee, M., Banerjee, S., Posner, M. C., Cartwright, C. A. 2010; 55 (7): 1852-1855

    View details for DOI 10.1007/s10620-010-1282-6

    View details for Web of Science ID 000278900200007

    View details for PubMedID 20499173

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