c-Src couples PI 3 kinase/Akt and MAPK signaling to PDGF-induced DNA synthesis in mesangial cells

Goutam Ghosh-choudhury, Lenin Mahimainathan, Falguni Das, Balachandar Venkatesan, Nandini Ghosh-choudhury

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Platelet-derived growth factor BB (PDGF) and PDGF receptor-β (PDGFR) play critical roles in mesangial cell proliferation during embryonic development and in mesangioproliferative glomerulonephritis. We have shown previously that phosphatidylinositol (PI) 3 kinase/Akt and Erk1/2 mitogen-activated protein kinase (MAPK) contribute to PDGF-dependent proliferation of mesangial cells, but the mechanism by which these two enzyme cascades are activated by PDGFR signaling is not precisely known. We examined the role of c-Src tyrosine kinase in this process. PDGF increased phosphorylation of c-Src in a time-dependent manner indicating its activation. A pharmacologic inhibitor of c-Src, PP1, blocked PDGF-induced DNA synthesis with concomitant inhibition of c-Src phosphorylation. Immunecomplex kinase assays of c-Src and PDGFR demonstrated inhibition of c-Src tyrosine kinase activity by PP1, without an effect on PDGFR tyrosine phosphorylation. Both PP1 and expression of dominant negative c-Src inhibited PDGF-induced PI 3 kinase, resulting in attenuation of Akt kinase activity. Expression of constitutively active c-Src increased Akt activity to the same extent as with PDGF. Constitutively active c-Src augmented PDGF-induced Akt activity, thus contributing to Akt signaling. Inhibition of c-Src tyrosine kinase blocked PDGF-stimulated MAPK activity and resulted in attenuation of c-fos gene transcription with concomitant prevention of Elk-1 transactivation. Furthermore, inhibition of c-Src increased p27Kip1 cyclin kinase inhibitor, and attenuated PDGF-induced pRb phosphorylation and CDK2 activity. These data provide the first evidence in mesangial cells that PDGF-activated c-Src tyrosine kinase relays signals to PI 3 kinase/Akt and MAPK. Furthermore our results demonstrate that c-Src integrates signals into the nucleus to activate CDK2, which is required for DNA synthesis.

Original languageEnglish (US)
Pages (from-to)1854-1864
Number of pages11
JournalCellular Signalling
Volume18
Issue number11
DOIs
StatePublished - Nov 2006

Fingerprint

Phosphatidylinositol 3-Kinase
Mesangial Cells
Mitogen-Activated Protein Kinases
DNA
Platelet-Derived Growth Factor Receptors
Phosphorylation
platelet-derived growth factor BB
Phosphotransferases
fos Genes
Cyclins
Mitogen-Activated Protein Kinase 1
Glomerulonephritis
Transcriptional Activation
Embryonic Development
Tyrosine

Keywords

  • c-fos
  • CDK2
  • DNA synthesis
  • PDGF
  • pRb

ASJC Scopus subject areas

  • Cell Biology

Cite this

c-Src couples PI 3 kinase/Akt and MAPK signaling to PDGF-induced DNA synthesis in mesangial cells. / Ghosh-choudhury, Goutam; Mahimainathan, Lenin; Das, Falguni; Venkatesan, Balachandar; Ghosh-choudhury, Nandini.

In: Cellular Signalling, Vol. 18, No. 11, 11.2006, p. 1854-1864.

Research output: Contribution to journalArticle

Ghosh-choudhury, Goutam ; Mahimainathan, Lenin ; Das, Falguni ; Venkatesan, Balachandar ; Ghosh-choudhury, Nandini. / c-Src couples PI 3 kinase/Akt and MAPK signaling to PDGF-induced DNA synthesis in mesangial cells. In: Cellular Signalling. 2006 ; Vol. 18, No. 11. pp. 1854-1864.
@article{0fd4817f29ce482a93a6742756cf0491,
title = "c-Src couples PI 3 kinase/Akt and MAPK signaling to PDGF-induced DNA synthesis in mesangial cells",
abstract = "Platelet-derived growth factor BB (PDGF) and PDGF receptor-β (PDGFR) play critical roles in mesangial cell proliferation during embryonic development and in mesangioproliferative glomerulonephritis. We have shown previously that phosphatidylinositol (PI) 3 kinase/Akt and Erk1/2 mitogen-activated protein kinase (MAPK) contribute to PDGF-dependent proliferation of mesangial cells, but the mechanism by which these two enzyme cascades are activated by PDGFR signaling is not precisely known. We examined the role of c-Src tyrosine kinase in this process. PDGF increased phosphorylation of c-Src in a time-dependent manner indicating its activation. A pharmacologic inhibitor of c-Src, PP1, blocked PDGF-induced DNA synthesis with concomitant inhibition of c-Src phosphorylation. Immunecomplex kinase assays of c-Src and PDGFR demonstrated inhibition of c-Src tyrosine kinase activity by PP1, without an effect on PDGFR tyrosine phosphorylation. Both PP1 and expression of dominant negative c-Src inhibited PDGF-induced PI 3 kinase, resulting in attenuation of Akt kinase activity. Expression of constitutively active c-Src increased Akt activity to the same extent as with PDGF. Constitutively active c-Src augmented PDGF-induced Akt activity, thus contributing to Akt signaling. Inhibition of c-Src tyrosine kinase blocked PDGF-stimulated MAPK activity and resulted in attenuation of c-fos gene transcription with concomitant prevention of Elk-1 transactivation. Furthermore, inhibition of c-Src increased p27Kip1 cyclin kinase inhibitor, and attenuated PDGF-induced pRb phosphorylation and CDK2 activity. These data provide the first evidence in mesangial cells that PDGF-activated c-Src tyrosine kinase relays signals to PI 3 kinase/Akt and MAPK. Furthermore our results demonstrate that c-Src integrates signals into the nucleus to activate CDK2, which is required for DNA synthesis.",
keywords = "c-fos, CDK2, DNA synthesis, PDGF, pRb",
author = "Goutam Ghosh-choudhury and Lenin Mahimainathan and Falguni Das and Balachandar Venkatesan and Nandini Ghosh-choudhury",
year = "2006",
month = "11",
doi = "10.1016/j.cellsig.2006.02.003",
language = "English (US)",
volume = "18",
pages = "1854--1864",
journal = "Cellular Signalling",
issn = "0898-6568",
publisher = "Elsevier Inc.",
number = "11",

}

TY - JOUR

T1 - c-Src couples PI 3 kinase/Akt and MAPK signaling to PDGF-induced DNA synthesis in mesangial cells

AU - Ghosh-choudhury, Goutam

AU - Mahimainathan, Lenin

AU - Das, Falguni

AU - Venkatesan, Balachandar

AU - Ghosh-choudhury, Nandini

PY - 2006/11

Y1 - 2006/11

N2 - Platelet-derived growth factor BB (PDGF) and PDGF receptor-β (PDGFR) play critical roles in mesangial cell proliferation during embryonic development and in mesangioproliferative glomerulonephritis. We have shown previously that phosphatidylinositol (PI) 3 kinase/Akt and Erk1/2 mitogen-activated protein kinase (MAPK) contribute to PDGF-dependent proliferation of mesangial cells, but the mechanism by which these two enzyme cascades are activated by PDGFR signaling is not precisely known. We examined the role of c-Src tyrosine kinase in this process. PDGF increased phosphorylation of c-Src in a time-dependent manner indicating its activation. A pharmacologic inhibitor of c-Src, PP1, blocked PDGF-induced DNA synthesis with concomitant inhibition of c-Src phosphorylation. Immunecomplex kinase assays of c-Src and PDGFR demonstrated inhibition of c-Src tyrosine kinase activity by PP1, without an effect on PDGFR tyrosine phosphorylation. Both PP1 and expression of dominant negative c-Src inhibited PDGF-induced PI 3 kinase, resulting in attenuation of Akt kinase activity. Expression of constitutively active c-Src increased Akt activity to the same extent as with PDGF. Constitutively active c-Src augmented PDGF-induced Akt activity, thus contributing to Akt signaling. Inhibition of c-Src tyrosine kinase blocked PDGF-stimulated MAPK activity and resulted in attenuation of c-fos gene transcription with concomitant prevention of Elk-1 transactivation. Furthermore, inhibition of c-Src increased p27Kip1 cyclin kinase inhibitor, and attenuated PDGF-induced pRb phosphorylation and CDK2 activity. These data provide the first evidence in mesangial cells that PDGF-activated c-Src tyrosine kinase relays signals to PI 3 kinase/Akt and MAPK. Furthermore our results demonstrate that c-Src integrates signals into the nucleus to activate CDK2, which is required for DNA synthesis.

AB - Platelet-derived growth factor BB (PDGF) and PDGF receptor-β (PDGFR) play critical roles in mesangial cell proliferation during embryonic development and in mesangioproliferative glomerulonephritis. We have shown previously that phosphatidylinositol (PI) 3 kinase/Akt and Erk1/2 mitogen-activated protein kinase (MAPK) contribute to PDGF-dependent proliferation of mesangial cells, but the mechanism by which these two enzyme cascades are activated by PDGFR signaling is not precisely known. We examined the role of c-Src tyrosine kinase in this process. PDGF increased phosphorylation of c-Src in a time-dependent manner indicating its activation. A pharmacologic inhibitor of c-Src, PP1, blocked PDGF-induced DNA synthesis with concomitant inhibition of c-Src phosphorylation. Immunecomplex kinase assays of c-Src and PDGFR demonstrated inhibition of c-Src tyrosine kinase activity by PP1, without an effect on PDGFR tyrosine phosphorylation. Both PP1 and expression of dominant negative c-Src inhibited PDGF-induced PI 3 kinase, resulting in attenuation of Akt kinase activity. Expression of constitutively active c-Src increased Akt activity to the same extent as with PDGF. Constitutively active c-Src augmented PDGF-induced Akt activity, thus contributing to Akt signaling. Inhibition of c-Src tyrosine kinase blocked PDGF-stimulated MAPK activity and resulted in attenuation of c-fos gene transcription with concomitant prevention of Elk-1 transactivation. Furthermore, inhibition of c-Src increased p27Kip1 cyclin kinase inhibitor, and attenuated PDGF-induced pRb phosphorylation and CDK2 activity. These data provide the first evidence in mesangial cells that PDGF-activated c-Src tyrosine kinase relays signals to PI 3 kinase/Akt and MAPK. Furthermore our results demonstrate that c-Src integrates signals into the nucleus to activate CDK2, which is required for DNA synthesis.

KW - c-fos

KW - CDK2

KW - DNA synthesis

KW - PDGF

KW - pRb

UR - http://www.scopus.com/inward/record.url?scp=33749267065&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33749267065&partnerID=8YFLogxK

U2 - 10.1016/j.cellsig.2006.02.003

DO - 10.1016/j.cellsig.2006.02.003

M3 - Article

C2 - 16530387

AN - SCOPUS:33749267065

VL - 18

SP - 1854

EP - 1864

JO - Cellular Signalling

JF - Cellular Signalling

SN - 0898-6568

IS - 11

ER -