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Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1

Trever G Bivona1, Ignacio Pérez De Castro, Ian M Ahearn

  • 1Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.

Nature
|July 8, 2003
PubMed

Insights

Ras proteins, crucial for cell growth and mutated in cancers, signal from the Golgi apparatus. This study reveals a distinct pathway for Golgi-localized Ras activation, impacting cell differentiation and radioresistance.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Ras proteins are key regulators of cellular growth and differentiation, frequently mutated in human cancers.
  • Ras signaling occurs at both the plasma membrane and the Golgi apparatus, but the mechanisms of compartmentalized signaling remain unclear.

Purpose of the Study:

  • To elucidate the mechanism of compartmentalized Ras signaling at the Golgi apparatus.
  • To determine the physiological role and consequences of Golgi-localized Ras activation.

Main Methods:

  • Investigated the translocation and activation of Ras guanine nucleotide exchange factor RasGRP1.
  • Utilized Src-dependent activation of phospholipase Cgamma1 and calcium ion (Ca2+) signaling.
  • Examined Ras activation in Jurkat cells following T-cell receptor stimulation and in PC12 cells.

Main Results:

  • Src-dependent activation of phospholipase Cgamma1 induced RasGRP1 translocation to the Golgi, activating Ras.
  • Calcium ions positively regulated Golgi Ras via RasGRP1 but negatively regulated plasma membrane Ras via CAPRI.
  • Ras activation was localized to the Golgi apparatus in Jurkat cells, demonstrating a physiological role for Golgi Ras.

Conclusions:

  • Golgi-localized Ras activation is mediated by a distinct pathway involving RasGRP1 and calcium ions.
  • Activation of Ras on the Golgi apparatus has significant biological consequences, including inducing cell differentiation and mediating radioresistance.
  • Compartmentalization of Ras signaling provides a mechanism for distinct cellular outcomes from the same signaling molecule.

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