LPA receptor signaling in colonic epithelia

Summary

Principal Investigator: CHANGHYON YUN
Affiliation: Emory University
Country: USA
Abstract: Our long-term goal is to understand the cellular signaling mechanisms in the intestinal epithelia with an emphasis on how protein-protein interaction affects the specificity and efficacy of signaling processes. Lysophosphatidic acid (LPA) has been shown to exert growth factor-like effects. Signaling by LPA is primarily mediated through a family of G-protein-coupled receptors, LPA^ LPA2 and LPA3. Despite more than a decade of study on LPA signaling, receptor subtype specific signaling and functions are not fully elucidated. However, this knowledge is a key to the rational design of therapeutic interventions targeting the novel intermediates and the pivotal pathways. We have recently found that there is an increase in LPA2 expression in several types of cancer, including colon cancer. This observation suggests that LPA2 is likely to play an essential pathophysiologic role that enhances cancer development and a better understanding of the signaling pathways and mechanism elicited by LPA2 is necessary. Our studies show that LPA activates the transcription factor KLF5, which is a promoter of cellular proliferation in the intestine, suggesting that KLF5 may be an intermediate transducing the biological effects of LPA. Recently, we and others have also shown that LPA2 interacts with a scaffold protein NHERF2. In addition, we have identified MAGI-3 as another LPA2 binding protein. Our preliminary studies show that the effects of MAGI-3 on LPA2-mediated signaling are unique and MAGI-3 negatively impacts the LPA-mediated signaling. Our data suggest that one reason for the divergence in LPA signaling under different conditions may be the presence or absence of interacting partners. Based on these data, we hypothesize that LPA2 facilitates tumor development in the colon by mediating multiple biological effects that promote proliferation and survival of cancer cells. We further hypothesize that the activity of LPA2 is regulated via the interaction with MAGI-3 and NHERF2. We propose the following studies. (1) We will define the biological effects mediated by LPA2 and the underlying mechanisms that enhance the formation of colorectal cancer. (2) We will determine the role of MAGI-3 in regulation of LPA2-mediated signaling in colon cancer cells. (3) We will delineate the effect of LPA and the LPA2 in vivo by using transgenic mice. Our studies will enhance our understanding of the importance and mechanism of tumorigenesis of colorectal cancer by LPA and LPA2 receptor. Our findings should help the therapeutic development against colorectal cancer.
Funding Period: 2009-09-20 - 2010-08-31
more information: NIH RePORT

Top Publications

  1. pmc Regulation of hypoxia-inducible factor 1α (HIF-1α) by lysophosphatidic acid is dependent on interplay between p53 and Krüppel-like factor 5
    Sei Jung Lee
    Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA
    J Biol Chem 288:25244-53. 2013
  2. pmc Regulation of expression and function of scavenger receptor class B, type I (SR-BI) by Na+/H+ exchanger regulatory factors (NHERFs)
    ZhiGang Hu
    Geriatric Research, Education and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA
    J Biol Chem 288:11416-35. 2013
  3. pmc Distinct phospholipase C-β isozymes mediate lysophosphatidic acid receptor 1 effects on intestinal epithelial homeostasis and wound closure
    Sei Jung Lee
    Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
    Mol Cell Biol 33:2016-28. 2013
  4. pmc Development of a unique small molecule modulator of CXCR4
    Zhongxing Liang
    Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia, United States of America
    PLoS ONE 7:e34038. 2012
  5. pmc MAGI-3 competes with NHERF-2 to negatively regulate LPA2 receptor signaling in colon cancer cells
    Sei Jung Lee
    Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Gastroenterology 140:924-34. 2011
  6. pmc Colorectal cancer cells - Proliferation, survival and invasion by lysophosphatidic acid
    Sei Jung Lee
    Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
    Int J Biochem Cell Biol 42:1907-10. 2010
  7. pmc The absence of LPA receptor 2 reduces the tumorigenesis by ApcMin mutation in the intestine
    Songbai Lin
    Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
    Am J Physiol Gastrointest Liver Physiol 299:G1128-38. 2010
  8. pmc Lysophosphatidic acid stimulates the intestinal brush border Na(+)/H(+) exchanger 3 and fluid absorption via LPA(5) and NHERF2
    Songbai Lin
    Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Gastroenterology 138:649-58. 2010
  9. pmc The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer
    Songbai Lin
    Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Gastroenterology 136:1711-20. 2009
  10. pmc Lysophosphatidic acid prevents apoptosis of Caco-2 colon cancer cells via activation of mitogen-activated protein kinase and phosphorylation of Bad
    Raluca Rusovici
    Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
    Biochim Biophys Acta 1770:1194-203. 2007

Detail Information

Publications13

  1. pmc Regulation of hypoxia-inducible factor 1α (HIF-1α) by lysophosphatidic acid is dependent on interplay between p53 and Krüppel-like factor 5
    Sei Jung Lee
    Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA
    J Biol Chem 288:25244-53. 2013
    ..These results identify KLF5 as a transactivator of HIF-1α and show that LPA regulates HIF-1α by dynamically modulating its interaction with KLF5 and p53. ..
  2. pmc Regulation of expression and function of scavenger receptor class B, type I (SR-BI) by Na+/H+ exchanger regulatory factors (NHERFs)
    ZhiGang Hu
    Geriatric Research, Education and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA
    J Biol Chem 288:11416-35. 2013
    ..Collectively, these data establish NHERF1 and NHERF2 as SR-BI protein binding partners that play a negative role in the regulation of SR-BI expression, selective CE transport, and steroidogenesis...
  3. pmc Distinct phospholipase C-β isozymes mediate lysophosphatidic acid receptor 1 effects on intestinal epithelial homeostasis and wound closure
    Sei Jung Lee
    Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
    Mol Cell Biol 33:2016-28. 2013
    ..These findings delineate novel LPA1-dependent lipid signaling that facilitates mucosal wound repair via spatial targeting of distinct PLC-βs within the cell...
  4. pmc Development of a unique small molecule modulator of CXCR4
    Zhongxing Liang
    Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia, United States of America
    PLoS ONE 7:e34038. 2012
    ..The unique function of CXCR4 is to promote the homing of tumor cells to their microenvironment at the distant organ sites...
  5. pmc MAGI-3 competes with NHERF-2 to negatively regulate LPA2 receptor signaling in colon cancer cells
    Sei Jung Lee
    Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Gastroenterology 140:924-34. 2011
    ..We investigated the roles of MAGI-3 and NHERF-2 in LPA(2)-mediated signaling in human colon cancer cells...
  6. pmc Colorectal cancer cells - Proliferation, survival and invasion by lysophosphatidic acid
    Sei Jung Lee
    Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
    Int J Biochem Cell Biol 42:1907-10. 2010
    ..This review provides a brief summary of recent advance on the effects of LPA on CRC cells...
  7. pmc The absence of LPA receptor 2 reduces the tumorigenesis by ApcMin mutation in the intestine
    Songbai Lin
    Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
    Am J Physiol Gastrointest Liver Physiol 299:G1128-38. 2010
    ..In summary, intestinal tumor initiated by Apc mutations is altered by LPA(2)-mediated signaling, which regulates tumor growth and survival by altering multiple targets...
  8. pmc Lysophosphatidic acid stimulates the intestinal brush border Na(+)/H(+) exchanger 3 and fluid absorption via LPA(5) and NHERF2
    Songbai Lin
    Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Gastroenterology 138:649-58. 2010
    ..We investigated the effect of lysophosphatidic acid (LPA) on Na(+)/H(+) exchanger activity and Na(+)-dependent fluid absorption in the intestine...
  9. pmc The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer
    Songbai Lin
    Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Gastroenterology 136:1711-20. 2009
    ..In this study, we sought to determine whether LPA and LPA2 regulate the progression of CC in vivo...
  10. pmc Lysophosphatidic acid prevents apoptosis of Caco-2 colon cancer cells via activation of mitogen-activated protein kinase and phosphorylation of Bad
    Raluca Rusovici
    Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
    Biochim Biophys Acta 1770:1194-203. 2007
    ..We further show that LPA treatment resulted in delayed activation of Erk. These results indicate that LPA protects Caco-2 cells from apoptotic insult by a mechanism involving Erk, Bad, and Bcl-2...
  11. pmc Lysophosphatidic acid facilitates proliferation of colon cancer cells via induction of Krüppel-like factor 5
    Huanchun Zhang
    Division of Digestive Diseases, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    J Biol Chem 282:15541-9. 2007
    ..These results identify KLF5 as a target of LPA-mediated signaling and suggest a role of KLF5 in promoting proliferation of intestinal epithelia in response to LPA...
  12. pmc Protein inhibitor of activated STAT1 interacts with and up-regulates activities of the pro-proliferative transcription factor Krüppel-like factor 5
    James X Du
    Division of Digestive Diseases, Department of Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    J Biol Chem 282:4782-93. 2007
    ..Importantly, PIAS1 increased the ability of KLF5 to enhance cell proliferation in transfected cells. These results indicate that PIAS1 is a functional partner of KLF5 and enhances the ability of KLF5 to promote proliferation...
  13. pmc MAGI-3 regulates LPA-induced activation of Erk and RhoA
    Huanchun Zhang
    Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
    Cell Signal 19:261-8. 2007
    ..These results demonstrate that MAGI-3 interacts directly with LPA(2) and regulates the ability of LPA(2) to activate Erk and RhoA...