Stability of prolactin receptor and prolactin signaling

Summary

Principal Investigator: SERGE FUCHS
Abstract: DESCRIPTION (provided by applicant): Pituitary hormone prolactin (PRL), which promotes growth and survival of mammary epithelial cells and plays a key role in breast tumorigenesis, acts through PRL receptor (PRLr). PRL signaling is controlled via down regulation of PRLr in response to the ligand via the mechanisms that are yet largely unknown. Our preliminary data suggest that (i) the bTrCP E3 ubiquitin ligase limits the extent of PRL signaling via PRLr ubiquitination and lysosomal degradation that depends on PRLr phosphorylation on Ser349, (ii) glycogen synthase kinase 3 (GSK3) is implicated in PRLr phosphorylation on Ser349, and (iii) this Ser349 phosphorylation as well as PRLr-bTrCP interaction and the proteolysis of PRLr are impaired in breast cancer cells. We hypothesize that GSK3-dependent phosphorylation of PRLr on Ser349 leads to the recruitment of bTrCP followed by ubiquitination, endocytosis/sorting and lysosomal degradation of PRLr to limit the extent of cellular responses to PRL. In breast cancers, oncogenic signaling-induced aberrations in PRLr phosphorylation and turnover might augment the extent of PRL signaling and promote PRL-mediated cell growth and survival. To test these hypotheses, we propose to: (1) Determine how PRLr stability is regulated in breast cancer cells and tissues that may exhibit impaired PRLr phosphorylation on Ser349;(2) Define the motifs required for PRLr endocytosis (internalization and post-internalization trafficking) and the role of bTrcp-dependent ubiquitination in these processes;(3) Determine whether GSK3, via its ability to phosphorylate PRLr on Ser349, plays a role in ubiquitination and degradation of PRLr and in the regulation of the extent of PRL signaling;(4) Determine whether stabilization of PRLr results in augmentation of the extent of responses to PRL in breast cells in vitro and in mice. Significance: these studies are important for our understanding of the events that occur in breast cancers and, therefore, are relevant to the mission of NCI. Completion of these experiments will potentially: (i). identify PRLr stabilization as a novel event in breast tumorigenesis;(ii) gain insight in the mechanisms underlying down regulation of hormone receptors and expand our knowledge on the mechanisms regulating the cellular responses to PRL, (iii) shed light on the role of PRLr stability in pathogenesis of breast cancer and offer new means for altering the levels of PRL-dependent survival of breast cancer cells.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Determinants of growth hormone receptor down-regulation
    Luqin Deng
    Department of Cell Biology, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294 0012, USA
    Mol Endocrinol 21:1537-51. 2007
  2. pmc Regulation of prolactin receptor levels and activity in breast cancer
    G Swaminathan
    Department of Animal Biology and Mari Lowe Center for Comparative Oncology Research, University of Pennsylvania, Philadelphia, PA 19104, USA
    J Mammary Gland Biol Neoplasia 13:81-91. 2008
  3. doi Prolactin stimulates ubiquitination, initial internalization, and degradation of its receptor via catalytic activation of Janus kinase 2
    Gayathri Swaminathan
    Department of Animal Biology and Mari Lowe Center for Comparative Oncology Research Cell, University of Pennsylvania, 380 S University Avenue, Philadelphia, Pennsylvania 19104, USA
    J Endocrinol 196:R1-7. 2008
  4. doi Oncogene-mediated inhibition of glycogen synthase kinase 3 beta impairs degradation of prolactin receptor
    Alexander Plotnikov
    Department of Animal Biology, University of Pennsylvania, Philadelphia, PA 19104 4539, USA
    Cancer Res 68:1354-61. 2008
  5. pmc Polyubiquitination of prolactin receptor stimulates its internalization, postinternalization sorting, and degradation via the lysosomal pathway
    Bentley Varghese
    Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, 380 S Philadelphia, PA 19104 4539, USA
    Mol Cell Biol 28:5275-87. 2008
  6. pmc Modulation of growth hormone receptor abundance and function: roles for the ubiquitin-proteasome system
    Stuart J Frank
    Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294 0012, USA
    Biochim Biophys Acta 1782:785-94. 2008
  7. pmc Prolactin inhibits activity of pyruvate kinase M2 to stimulate cell proliferation
    Bentley Varghese
    Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 4539, USA
    Mol Endocrinol 24:2356-65. 2010
  8. pmc The role of prolactin receptor in GH signaling in breast cancer cells
    Jie Xu
    Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    Mol Endocrinol 27:266-79. 2013
  9. pmc Impaired turnover of prolactin receptor contributes to transformation of human breast cells
    Alexandr Plotnikov
    Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 4539, USA
    Cancer Res 69:3165-72. 2009
  10. pmc Ubiquitination-dependent regulation of signaling receptors in cancer
    Wei Chun HuangFu
    Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Genes Cancer 1:725-34. 2010

Detail Information

Publications10

  1. ncbi Determinants of growth hormone receptor down-regulation
    Luqin Deng
    Department of Cell Biology, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294 0012, USA
    Mol Endocrinol 21:1537-51. 2007
    ..The latter requires GH-induced JAK2 activation and GHR tyrosine phosphorylation and is correlated to GHR ubiquitination in our reconstitution system...
  2. pmc Regulation of prolactin receptor levels and activity in breast cancer
    G Swaminathan
    Department of Animal Biology and Mari Lowe Center for Comparative Oncology Research, University of Pennsylvania, Philadelphia, PA 19104, USA
    J Mammary Gland Biol Neoplasia 13:81-91. 2008
    ....
  3. doi Prolactin stimulates ubiquitination, initial internalization, and degradation of its receptor via catalytic activation of Janus kinase 2
    Gayathri Swaminathan
    Department of Animal Biology and Mari Lowe Center for Comparative Oncology Research Cell, University of Pennsylvania, 380 S University Avenue, Philadelphia, Pennsylvania 19104, USA
    J Endocrinol 196:R1-7. 2008
    ..We discuss how Jak2-mediated signaling might be transduced into Ser349 phosphorylation of PRLr as well as its ubiquitination and endocytosis...
  4. doi Oncogene-mediated inhibition of glycogen synthase kinase 3 beta impairs degradation of prolactin receptor
    Alexander Plotnikov
    Department of Animal Biology, University of Pennsylvania, Philadelphia, PA 19104 4539, USA
    Cancer Res 68:1354-61. 2008
    ....
  5. pmc Polyubiquitination of prolactin receptor stimulates its internalization, postinternalization sorting, and degradation via the lysosomal pathway
    Bentley Varghese
    Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, 380 S Philadelphia, PA 19104 4539, USA
    Mol Cell Biol 28:5275-87. 2008
    ..We discuss how specific ubiquitination may regulate early and late stages of endocytosis of PRLr and of related receptors to contribute to the negative regulation of the magnitude and duration of downstream signaling...
  6. pmc Modulation of growth hormone receptor abundance and function: roles for the ubiquitin-proteasome system
    Stuart J Frank
    Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294 0012, USA
    Biochim Biophys Acta 1782:785-94. 2008
    ....
  7. pmc Prolactin inhibits activity of pyruvate kinase M2 to stimulate cell proliferation
    Bentley Varghese
    Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 4539, USA
    Mol Endocrinol 24:2356-65. 2010
    ..We discuss a hypothesis that the inhibition of PKM2 by PRL contributes to the PRL-stimulated cell proliferation...
  8. pmc The role of prolactin receptor in GH signaling in breast cancer cells
    Jie Xu
    Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    Mol Endocrinol 27:266-79. 2013
    ..Our data suggest that PRLR's presence meaningfully affects GHR use in breast cancer cells...
  9. pmc Impaired turnover of prolactin receptor contributes to transformation of human breast cells
    Alexandr Plotnikov
    Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 4539, USA
    Cancer Res 69:3165-72. 2009
    ..Consequences of alteration of PRLr turnover for homeostasis of mammary cells and development of breast cancers, as well as the utility of therapies that target PRLr function in these malignancies, are discussed...
  10. pmc Ubiquitination-dependent regulation of signaling receptors in cancer
    Wei Chun HuangFu
    Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Genes Cancer 1:725-34. 2010
    ..These mechanisms as well as their significance for the treatment of human cancers are discussed...