PDGF Regulation of Cell Growth and Death

Summary

Principal Investigator: Hyeong Reh Kim
Abstract: DESCRIPTION: (provided by applicant) The long-term objective of this research project is to unveil the molecular and cellular mechanisms by which different forms of the platelet-derived growth factor (PDGF) regulate a diverse array of cellular processes including cell proliferation, migration, transformation and apoptosis. PDGF exerts its cellular effects by activating two structurally related cell surface receptor tyrosine kinases (a-PDGFR and beta-PDGFR). Although a number of signaling molecules activated by these receptors have been identified, little is known about which signaling pathways are a- or beta-PDGFR-specific, and how these signals are integrated to agonize or antagonize specific cellular processes. During the last funding period, we have investigated a- and beta-PDGFR-specific signaling pathways critical for PDGF-specific cellular processes. We have found that a-PDGFR antagonizes beta-PDGFR-mediated transformation through JNK-1 activation, while both a- and beta-receptors effectively activate ERKs and trigger the cell cycle. These results revealed a striking feature of PDGF signaling: that the specificity and the strength of the PDGF-growth signal is modulated by a-PDGFR-mediated simultaneous activation of stimulatory and inhibitory signals, whereas beta-PDGFR mainly induces a stimulatory signal. The preliminary studies show that a-PDGFR is required for cell cycle arrest at G1, and that a-PDGFR-activated iNK-i induces p21 WAF 1/CIP1 (an inhibitor of cell cycle) expression and enhances caspase (an initiator of apoptosis) activation, providing a mechanistic insight for a-PDGFR-mediated growth inhibitory signals. Based on these observations, we hypothesize that a-PDGFR signaling is critical for PDGF regulation of apoptosis and cell cycle checkpoint, and that JNK-1 is an essential component for the a-PDGFR mediated negative signal. To test our hypothesis, we propose (1) to investigate the molecular mechanism by which aPDGFR, but not beta-PDGFR, activates JNK-1; (2) to investigate a-PDGFR- and beta-PDGFR-specific cell cycle regulation; (3) to investigate the molecular mechanisms by which JNK-1 regulates apoptosis; and (4) to further investigate the a-PDGFR signaling pathways induced by different PDGF isoforms in normal and tumor cells. The accomplishment of these aims will help in unveiling the molecular and cellular mechanisms governing the specificity of growth factor signaling, and greatly contribute to the collective endeavor to understand the role of PDGF signaling in physiological and pathological conditions.
Funding Period: 1996-07-15 - 2008-02-28
more information: NIH RePORT

Top Publications

  1. pmc Differential tumorigenic potential and matriptase activation between PDGF B versus PDGF D in prostate cancer
    Abdo J Najy
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Mol Cancer Res 10:1087-97. 2012
  2. pmc A novel signaling axis of matriptase/PDGF-D/ß-PDGFR in human prostate cancer
    Carolyn V Ustach
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA
    Cancer Res 70:9631-40. 2010
  3. pmc Platelet-derived growth factor-C (PDGF-C) activation by serine proteases: implications for breast cancer progression
    Newton J Hurst
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State School of Medicine, Detroit, MI 48201, USA
    Biochem J 441:909-18. 2012
  4. pmc PTEN regulates PDGF ligand switch for β-PDGFR signaling in prostate cancer
    M Katie Conley-LaComb
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA
    Am J Pathol 180:1017-27. 2012

Detail Information

Publications4

  1. pmc Differential tumorigenic potential and matriptase activation between PDGF B versus PDGF D in prostate cancer
    Abdo J Najy
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Mol Cancer Res 10:1087-97. 2012
    ....
  2. pmc A novel signaling axis of matriptase/PDGF-D/ß-PDGFR in human prostate cancer
    Carolyn V Ustach
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA
    Cancer Res 70:9631-40. 2010
    ..This study unveiled a novel signaling axis of matriptase/PDGF-D/β-PDGFR in PCa, providing new insights into functional interplay between serine protease and growth factor signaling networks...
  3. pmc Platelet-derived growth factor-C (PDGF-C) activation by serine proteases: implications for breast cancer progression
    Newton J Hurst
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State School of Medicine, Detroit, MI 48201, USA
    Biochem J 441:909-18. 2012
    ..Lastly, we provide evidence suggesting a two-step proteolytic processing of PDGF-C involving creation of a hemidimer, followed by GFD-D (growth factor domain dimer) generation...
  4. pmc PTEN regulates PDGF ligand switch for β-PDGFR signaling in prostate cancer
    M Katie Conley-LaComb
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA
    Am J Pathol 180:1017-27. 2012
    ..Taken together, these results suggest a mechanism by which loss of PTEN may promote prostate cancer progression via PDGF D/β-PDGFR signal transduction...