Guanine nucleotide exchange factors

Activators of Ras superfamily proteins

A. F. Overbeck, T. R. Brtva, A. D. Cox, S. M. Graham, S. Y. Huff, R. Khosravi-Far, Lawrence Quilliam, P. A. Solski, C. J. Der

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Members of the Ras superfamily of proteins function as regulated GDP/GTP switches that cycle between active GTP-complexed and inactive GDP-complexed states Guanine nucleotide exchange factors (GEFs) stimulate formation of the GTP-bound state, whereas GTPase activating proteins (GAPs) catalyze the formation of the GDP-bound state. We describe three studies that evaluate the mechanism of action of GEFs for Ras (SOS1 and RasGRF/CDC25) or Ras-related Rho (Dbl and Vav) proteins. Growth factor mediated activation of Ras is believed to be mediated by activation of Ras GEFs (CDC25/GRF and SOS1/2). Although the mechanisms of Ras GEF regulation are unclear, recent studies suggest that translocation of SOS1 to the plasma membrane, where Ras is located, might be responsible for Ras activation. Our observation that the addition of the Ras plasma membrane-targeting sequence to the catalytic domains of CDC25 and SOS1 greatly enhanced their transforming and transactivation activities (10-50 fold and 5-10 fold, respectively) suggests that membrane translocation alone is sufficient to potentiate GEF activation of Ras. We have determined that two Ras-related proteins, designated R-Ras and R Ras2/TC21, can trigger the malignant transformation of NIH 3T3 cells via activation of the Ras signal transduction pathway. Furthermore, like Ras and R-Ras, we observed that TC21 GTPase activity was stimulated by Ras GAPs. However, we observed that both SOS1 and CDC25 were activators of normal TC21, but not R-Ras, transforming activities. Therefore, TC21, but not R-Ras, may be activated by the same extracellular signaling events that activate Ras proteins. Dbl family proteins are believed to function as GEFs and activators of the Ras-related Rho family of proteins. However, one Dbl family oncogene. designated Vav, has been reported to be a GEF for Ras proteins. Therefore we were interested in determining whether Dbl family oncogenes cause transformation by triggering the constitutive activation of Rho or Ras proteins. Our results suggest that Dbl oncogenes cause transformation via a Ras-independent activation of MAP kinases and Rho family proteins.

Original languageEnglish (US)
Pages (from-to)468-476
Number of pages9
JournalMolecular Reproduction and Development
Volume42
Issue number4
DOIs
StatePublished - 1995
Externally publishedYes

Fingerprint

ras Guanine Nucleotide Exchange Factors
Guanine Nucleotide Exchange Factors
ras Proteins
Guanosine Triphosphate
Oncogenes
Guanine Nucleotide-Releasing Factor 2
Proteins
ras GTPase-Activating Proteins
Cell Membrane
GTPase-Activating Proteins
NIH 3T3 Cells
GTP Phosphohydrolases
Transcriptional Activation
Signal Transduction
Catalytic Domain
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Membranes

Keywords

  • CDC25
  • Dbl
  • Ras-related proteins

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

Overbeck, A. F., Brtva, T. R., Cox, A. D., Graham, S. M., Huff, S. Y., Khosravi-Far, R., ... Der, C. J. (1995). Guanine nucleotide exchange factors: Activators of Ras superfamily proteins. Molecular Reproduction and Development, 42(4), 468-476. https://doi.org/10.1002/mrd.1080420415

Guanine nucleotide exchange factors : Activators of Ras superfamily proteins. / Overbeck, A. F.; Brtva, T. R.; Cox, A. D.; Graham, S. M.; Huff, S. Y.; Khosravi-Far, R.; Quilliam, Lawrence; Solski, P. A.; Der, C. J.

In: Molecular Reproduction and Development, Vol. 42, No. 4, 1995, p. 468-476.

Research output: Contribution to journalArticle

Overbeck, AF, Brtva, TR, Cox, AD, Graham, SM, Huff, SY, Khosravi-Far, R, Quilliam, L, Solski, PA & Der, CJ 1995, 'Guanine nucleotide exchange factors: Activators of Ras superfamily proteins', Molecular Reproduction and Development, vol. 42, no. 4, pp. 468-476. https://doi.org/10.1002/mrd.1080420415
Overbeck, A. F. ; Brtva, T. R. ; Cox, A. D. ; Graham, S. M. ; Huff, S. Y. ; Khosravi-Far, R. ; Quilliam, Lawrence ; Solski, P. A. ; Der, C. J. / Guanine nucleotide exchange factors : Activators of Ras superfamily proteins. In: Molecular Reproduction and Development. 1995 ; Vol. 42, No. 4. pp. 468-476.
@article{d0ad38e70ad4427b8051b017135314ea,
title = "Guanine nucleotide exchange factors: Activators of Ras superfamily proteins",
abstract = "Members of the Ras superfamily of proteins function as regulated GDP/GTP switches that cycle between active GTP-complexed and inactive GDP-complexed states Guanine nucleotide exchange factors (GEFs) stimulate formation of the GTP-bound state, whereas GTPase activating proteins (GAPs) catalyze the formation of the GDP-bound state. We describe three studies that evaluate the mechanism of action of GEFs for Ras (SOS1 and RasGRF/CDC25) or Ras-related Rho (Dbl and Vav) proteins. Growth factor mediated activation of Ras is believed to be mediated by activation of Ras GEFs (CDC25/GRF and SOS1/2). Although the mechanisms of Ras GEF regulation are unclear, recent studies suggest that translocation of SOS1 to the plasma membrane, where Ras is located, might be responsible for Ras activation. Our observation that the addition of the Ras plasma membrane-targeting sequence to the catalytic domains of CDC25 and SOS1 greatly enhanced their transforming and transactivation activities (10-50 fold and 5-10 fold, respectively) suggests that membrane translocation alone is sufficient to potentiate GEF activation of Ras. We have determined that two Ras-related proteins, designated R-Ras and R Ras2/TC21, can trigger the malignant transformation of NIH 3T3 cells via activation of the Ras signal transduction pathway. Furthermore, like Ras and R-Ras, we observed that TC21 GTPase activity was stimulated by Ras GAPs. However, we observed that both SOS1 and CDC25 were activators of normal TC21, but not R-Ras, transforming activities. Therefore, TC21, but not R-Ras, may be activated by the same extracellular signaling events that activate Ras proteins. Dbl family proteins are believed to function as GEFs and activators of the Ras-related Rho family of proteins. However, one Dbl family oncogene. designated Vav, has been reported to be a GEF for Ras proteins. Therefore we were interested in determining whether Dbl family oncogenes cause transformation by triggering the constitutive activation of Rho or Ras proteins. Our results suggest that Dbl oncogenes cause transformation via a Ras-independent activation of MAP kinases and Rho family proteins.",
keywords = "CDC25, Dbl, Ras-related proteins",
author = "Overbeck, {A. F.} and Brtva, {T. R.} and Cox, {A. D.} and Graham, {S. M.} and Huff, {S. Y.} and R. Khosravi-Far and Lawrence Quilliam and Solski, {P. A.} and Der, {C. J.}",
year = "1995",
doi = "10.1002/mrd.1080420415",
language = "English (US)",
volume = "42",
pages = "468--476",
journal = "Molecular Reproduction and Development",
issn = "1040-452X",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - Guanine nucleotide exchange factors

T2 - Activators of Ras superfamily proteins

AU - Overbeck, A. F.

AU - Brtva, T. R.

AU - Cox, A. D.

AU - Graham, S. M.

AU - Huff, S. Y.

AU - Khosravi-Far, R.

AU - Quilliam, Lawrence

AU - Solski, P. A.

AU - Der, C. J.

PY - 1995

Y1 - 1995

N2 - Members of the Ras superfamily of proteins function as regulated GDP/GTP switches that cycle between active GTP-complexed and inactive GDP-complexed states Guanine nucleotide exchange factors (GEFs) stimulate formation of the GTP-bound state, whereas GTPase activating proteins (GAPs) catalyze the formation of the GDP-bound state. We describe three studies that evaluate the mechanism of action of GEFs for Ras (SOS1 and RasGRF/CDC25) or Ras-related Rho (Dbl and Vav) proteins. Growth factor mediated activation of Ras is believed to be mediated by activation of Ras GEFs (CDC25/GRF and SOS1/2). Although the mechanisms of Ras GEF regulation are unclear, recent studies suggest that translocation of SOS1 to the plasma membrane, where Ras is located, might be responsible for Ras activation. Our observation that the addition of the Ras plasma membrane-targeting sequence to the catalytic domains of CDC25 and SOS1 greatly enhanced their transforming and transactivation activities (10-50 fold and 5-10 fold, respectively) suggests that membrane translocation alone is sufficient to potentiate GEF activation of Ras. We have determined that two Ras-related proteins, designated R-Ras and R Ras2/TC21, can trigger the malignant transformation of NIH 3T3 cells via activation of the Ras signal transduction pathway. Furthermore, like Ras and R-Ras, we observed that TC21 GTPase activity was stimulated by Ras GAPs. However, we observed that both SOS1 and CDC25 were activators of normal TC21, but not R-Ras, transforming activities. Therefore, TC21, but not R-Ras, may be activated by the same extracellular signaling events that activate Ras proteins. Dbl family proteins are believed to function as GEFs and activators of the Ras-related Rho family of proteins. However, one Dbl family oncogene. designated Vav, has been reported to be a GEF for Ras proteins. Therefore we were interested in determining whether Dbl family oncogenes cause transformation by triggering the constitutive activation of Rho or Ras proteins. Our results suggest that Dbl oncogenes cause transformation via a Ras-independent activation of MAP kinases and Rho family proteins.

AB - Members of the Ras superfamily of proteins function as regulated GDP/GTP switches that cycle between active GTP-complexed and inactive GDP-complexed states Guanine nucleotide exchange factors (GEFs) stimulate formation of the GTP-bound state, whereas GTPase activating proteins (GAPs) catalyze the formation of the GDP-bound state. We describe three studies that evaluate the mechanism of action of GEFs for Ras (SOS1 and RasGRF/CDC25) or Ras-related Rho (Dbl and Vav) proteins. Growth factor mediated activation of Ras is believed to be mediated by activation of Ras GEFs (CDC25/GRF and SOS1/2). Although the mechanisms of Ras GEF regulation are unclear, recent studies suggest that translocation of SOS1 to the plasma membrane, where Ras is located, might be responsible for Ras activation. Our observation that the addition of the Ras plasma membrane-targeting sequence to the catalytic domains of CDC25 and SOS1 greatly enhanced their transforming and transactivation activities (10-50 fold and 5-10 fold, respectively) suggests that membrane translocation alone is sufficient to potentiate GEF activation of Ras. We have determined that two Ras-related proteins, designated R-Ras and R Ras2/TC21, can trigger the malignant transformation of NIH 3T3 cells via activation of the Ras signal transduction pathway. Furthermore, like Ras and R-Ras, we observed that TC21 GTPase activity was stimulated by Ras GAPs. However, we observed that both SOS1 and CDC25 were activators of normal TC21, but not R-Ras, transforming activities. Therefore, TC21, but not R-Ras, may be activated by the same extracellular signaling events that activate Ras proteins. Dbl family proteins are believed to function as GEFs and activators of the Ras-related Rho family of proteins. However, one Dbl family oncogene. designated Vav, has been reported to be a GEF for Ras proteins. Therefore we were interested in determining whether Dbl family oncogenes cause transformation by triggering the constitutive activation of Rho or Ras proteins. Our results suggest that Dbl oncogenes cause transformation via a Ras-independent activation of MAP kinases and Rho family proteins.

KW - CDC25

KW - Dbl

KW - Ras-related proteins

UR - http://www.scopus.com/inward/record.url?scp=0028863504&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028863504&partnerID=8YFLogxK

U2 - 10.1002/mrd.1080420415

DO - 10.1002/mrd.1080420415

M3 - Article

VL - 42

SP - 468

EP - 476

JO - Molecular Reproduction and Development

JF - Molecular Reproduction and Development

SN - 1040-452X

IS - 4

ER -