title: A positive feedback loop involving Erk5 and Akt turns on mesangial cell proliferation in response to PDGF.
abstract: Platelet-derived growth factor BB and its receptor (PDGFRβ) play a pivotal role in the development of renal glomerular mesangial cells. Their roles in increased mesangial cell proliferation during mesangioproliferative glomerulonephritis have long been noted, but the operating logic of signaling mechanisms regulating these changes remains poorly understood. We examined the role of a recently identified MAPK, Erk5, in this process. PDGF increased the activating phosphorylation of Erk5 and tyrosine phosphorylation of proteins in a time-dependent manner. A pharmacologic inhibitor of Erk5, XMD8-92, abrogated PDGF-induced DNA synthesis and mesangial cell proliferation. Similarly, expression of dominant negative Erk5 or siRNAs against Erk5 blocked PDGF-stimulated DNA synthesis and proliferation. Inhibition of Erk5 attenuated expression of cyclin D1 mRNA and protein, resulting in suppression of CDK4-mediated phosphorylation of the tumor suppressor protein pRb. Expression of cyclin D1 or CDK4 prevented the dominant negative Erk5- or siErk5-mediated inhibition of DNA synthesis and mesangial cell proliferation induced by PDGF. We have previously shown that phosphatidylinositol 3-kinase (PI3-kinase) contributes to PDGF-induced proliferation of mesangial cells. Inhibition of PI3-kinase blocked PDGF-induced phosphorylation of Erk5. Since PI3-kinase acts through Akt, we determined the role of Erk5 on Akt phosphorylation. XMD8-92, dominant negative Erk5, and siErk5 inhibited phosphorylation of Akt by PDGF. Interestingly, we found inhibition of PDGF-induced Erk5 phosphorylation by a pharmacological inhibitor of Akt kinase and kinase dead Akt in mesangial cells. Thus our data unfold the presence of a positive feedback microcircuit between Erk5 and Akt downstream of PI3-kinase nodal point for PDGF-induced mesangial cell proliferation.
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas; and.
authors.forename: Amit
authors.initials: A
authors.lastname: Bera
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas; and.
authors.forename: Falguni
authors.initials: F
authors.lastname: Das
authors.affiliation: Veterans Administration Research Service, South Texas Veterans Health Care System, San Antonio, Texas; Department of Pathology, University of Texas Health Science Center, San Antonio, Texas; choudhuryg@uthscsa.edu.
authors.forename: Nandini
authors.initials: N
authors.lastname: Ghosh-Choudhury
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas; and.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas; and.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Pal
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas; and.
authors.forename: Yves
authors.initials: Y
authors.lastname: Gorin
authors.affiliation: Veterans Administration Research Service, South Texas Veterans Health Care System, San Antonio, Texas; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas; and.
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
authors.affiliation: Veterans Administration Research Service, South Texas Veterans Health Care System, San Antonio, Texas; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas; and.
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
authors.affiliation: Veterans Administration Research Service, South Texas Veterans Health Care System, San Antonio, Texas; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas; and Geriatric Research, Education, and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas.
authors.forename: Goutam
authors.initials: G
authors.lastname: Ghosh Choudhury
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism*; D048054:Mitogen-Activated Protein Kinase 7 / Q000096:biosynthesis*; D051058:Oncogene Protein v-akt / Q000096:biosynthesis*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D051381:Rats
chemical_list: D010982:Platelet-Derived Growth Factor; D051058:Oncogene Protein v-akt; D048054:Mitogen-Activated Protein Kinase 7
keywords: Akt kinase; MAP kinase; cell proliferation; receptor tyrosine kinase; renal physiology
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