Regulation of beta1 integrin glycosylation by ras

Summary

Principal Investigator: Susan Bellis
Affiliation: University of Alabama at Birmingham
Country: USA
Abstract: Much of the mortality associated with cancer results from uncontrolled metastasis of the primary tumor. Metastasis is a poorly-understood process, for which there are few effective treatments. It is well-accepted that tumor cell association with the extracellular matrix comprises an important factor in metastasis, and in turn, this interaction is regulated by cell adhesion receptors such as integrins. Work from our laboratory has identified a novel mechanism for regulation of the beta l subfamily of integrin receptors. In particular, we have found that beta l integrin function is modulated by the acquisition of alpha 2-6 sialic acids, a sugar structure added by ST6Gal I, a sialyl transferase which has long been implicated in the progression/metastasis of colon carcinoma. Our work suggests that ST6Gal I, and accordingly, integrin alpha 2-6 sialylation, are upregulated in tumor cell lines that have oncogenic ras, as well as in human colon tumors. In vitro studies further suggest that integrin sialylation has a marked on the adhesion, migration and invasiveness of colon tumor cells. To better understand the contribution of sialylation to integrin structure/function, as well as the potential role of integrin sialylation in tumor cell metastasis, we have proposed the following aims: Specific Aim 1: Influence of site-specific glycosylation on integrin conformation and function. As part of this aim, we will characterize the conformation and function of integrins that have each of the individual N- glycosylation sites ablated. Specific Aim 2: Effects of integrin sialylation on galectin-3-regulated cell behaviors. We will examine the role of integrin sialylation in regulating gal-3 - induced cellular responses including adhesion, migration, invasion and apoptosis. Specific Aim 3: Modulation of metastasis-related cell behaviors by ras-directed differential sialylation. These studies aim to determine whether integrin sialylation serves as a downstream effector of ras in mediating behaviors such as anchorage-independent growth and invasion. Specific Aim 4: Role of integrin sialylation in promoting tumor growth and/or metastasis in nude mice. We will monitor tumorigenesis and metastasis of cells with variant levels of integrin sialylation.
Funding Period: ----------------1999 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. pmc Proteolytic shedding of ST6Gal-I by BACE1 regulates the glycosylation and function of alpha4beta1 integrins
    Alencia V Woodard-Grice
    Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Biol Chem 283:26364-73. 2008
  2. pmc Sialylation of beta1 integrins blocks cell adhesion to galectin-3 and protects cells against galectin-3-induced apoptosis
    Ya Zhuo
    Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Biol Chem 283:22177-85. 2008
  3. pmc Tumor cell migration and invasion are regulated by expression of variant integrin glycoforms
    Faheem M Shaikh
    Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    Exp Cell Res 314:2941-50. 2008
  4. pmc Regulation of the metastatic cell phenotype by sialylated glycans
    Matthew J Schultz
    Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, MCLM 982A 1918 University Boulevard, Birmingham, AL 35294 0005, USA
    Cancer Metastasis Rev 31:501-18. 2012
  5. pmc ST6Gal-I protein expression is upregulated in human epithelial tumors and correlates with stem cell markers in normal tissues and colon cancer cell lines
    Amanda F Swindall
    Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Cancer Res 73:2368-78. 2013
  6. pmc Emerging role of alpha2,6-sialic acid as a negative regulator of galectin binding and function
    Ya Zhuo
    Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Biol Chem 286:5935-41. 2011
  7. pmc Sialylation of the Fas death receptor by ST6Gal-I provides protection against Fas-mediated apoptosis in colon carcinoma cells
    Amanda F Swindall
    Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Biol Chem 286:22982-90. 2011
  8. pmc ST6Gal-I regulates macrophage apoptosis via α2-6 sialylation of the TNFR1 death receptor
    Zhongyu Liu
    Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Biol Chem 286:39654-62. 2011

Detail Information

Publications8

  1. pmc Proteolytic shedding of ST6Gal-I by BACE1 regulates the glycosylation and function of alpha4beta1 integrins
    Alencia V Woodard-Grice
    Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Biol Chem 283:26364-73. 2008
    ..Collectively, these results describe a novel mechanism for alpha4beta1 regulation and further suggest an unanticipated role for BACE1 in macrophage function...
  2. pmc Sialylation of beta1 integrins blocks cell adhesion to galectin-3 and protects cells against galectin-3-induced apoptosis
    Ya Zhuo
    Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Biol Chem 283:22177-85. 2008
    ....
  3. pmc Tumor cell migration and invasion are regulated by expression of variant integrin glycoforms
    Faheem M Shaikh
    Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    Exp Cell Res 314:2941-50. 2008
    ....
  4. pmc Regulation of the metastatic cell phenotype by sialylated glycans
    Matthew J Schultz
    Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, MCLM 982A 1918 University Boulevard, Birmingham, AL 35294 0005, USA
    Cancer Metastasis Rev 31:501-18. 2012
    ..The goal of this review is to highlight selected examples of sialylated glycans for which there is some knowledge of molecular mechanisms linking aberrant sialylation to critical processes involved in metastasis...
  5. pmc ST6Gal-I protein expression is upregulated in human epithelial tumors and correlates with stem cell markers in normal tissues and colon cancer cell lines
    Amanda F Swindall
    Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Cancer Res 73:2368-78. 2013
    ..Collectively, our results suggest that ST6Gal-I promotes tumorigenesis and may serve as a regulator of the stem cell phenotype in both normal and cancer cell populations...
  6. pmc Emerging role of alpha2,6-sialic acid as a negative regulator of galectin binding and function
    Ya Zhuo
    Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Biol Chem 286:5935-41. 2011
    ..This minireview summarizes the evidence suggesting that ST6Gal-I activity serves as an "off switch" for galectin function...
  7. pmc Sialylation of the Fas death receptor by ST6Gal-I provides protection against Fas-mediated apoptosis in colon carcinoma cells
    Amanda F Swindall
    Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Biol Chem 286:22982-90. 2011
    ..This finding establishes a new paradigm by which death receptor function is impaired for the self-protection of tumors against apoptosis...
  8. pmc ST6Gal-I regulates macrophage apoptosis via α2-6 sialylation of the TNFR1 death receptor
    Zhongyu Liu
    Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Biol Chem 286:39654-62. 2011
    ....