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SmgGDS is a guanine nucleotide exchange factor that specifically activates RhoA and RhoC

Brant Hamel1, Elizabeth Monaghan-Benson, Rafael J Rojas

  • 1Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365, USA.

The Journal of Biological Chemistry
|January 19, 2011
PubMed

Insights

SmgGDS specifically activates RhoA and RhoC, unlike other guanine nucleotide exchange factors (GEFs). This protein utilizes a unique catalytic mechanism, distinct from canonical GEFs, highlighting its specific role in cellular processes.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • SmgGDS (Son of sevenless, Dbl-like guanine nucleotide exchange factor) is an atypical GEF.
  • It is implicated in cell proliferation, migration, and cancer.
  • Previous studies showed SmgGDS activates various small GTPases, including Ras and Rho family members.

Purpose of the Study:

  • To investigate the specific GTPase targets of SmgGDS.
  • To elucidate the unique catalytic mechanism of SmgGDS.
  • To confirm the in vivo specificity of SmgGDS activity.

Main Methods:

  • Purified GTPase activation assays.
  • Mutational analysis of SmgGDS.
  • Homology modeling of SmgGDS.
  • In vitro and in cellulo specificity assays.

Main Results:

  • SmgGDS exclusively activates RhoA and RhoC among tested GTPases.
  • Activation is catalytic and preferential for nucleotide-depleted RhoA.
  • SmgGDS employs a distinct exchange mechanism, requiring RhoA's polybasic region.
  • Mutations in SmgGDS's electronegative surface patch or binding groove abolish RhoA activation.
  • In vitro specificity for RhoA and RhoC is maintained in cellular contexts.

Conclusions:

  • SmgGDS is a bona fide GEF with specific activity towards RhoA and RhoC.
  • It utilizes a novel activation mechanism distinct from other Rho family GEFs.
  • This specificity and unique mechanism have implications for understanding SmgGDS function in cancer and cell signaling.

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