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Ras mediates the cAMP‐dependent activation of extracellular signal‐regulated kinases (ERKs) in melanocytes
Author(s) -
Buscà Roser,
Abbe Patricia,
Mantoux Fréderic,
Aberdam Edith,
Peyssonnaux Carole,
Eychène Alain,
Ortonne JeanPaul,
Ballotti Robert
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.12.2900
Subject(s) - nice , kinase , medicine , library science , humanities , computer science , philosophy , chemistry , biochemistry , programming language
In melanocytes and melanoma cells, cAMP activates extracellular signal‐regulated kinases (ERKs) and MEK‐1 by an unknown mechanism. We demonstrate that B‐Raf is activated by cAMP in melanocytes. A dominant‐negative mutant of B‐Raf, but not of Raf‐1, blocked the cAMP‐induced activation of ERK, indicating that B‐Raf is the MEK‐1 upstream regulator mediating this cAMP effect. Studies using Clostridium sordelii lethal toxin and Clostridium difficile toxin B have suggested that Rap‐1 or Ras might transduce cAMP action. We show that Ras, but not Rap‐1, is activated cell‐specifically and mediates the cAMP‐dependent activation of ERKs, while Rap‐1 is not involved in this process in melanocytes. Our results suggest a novel, cell‐specific mechanism involving Ras small GTPase and B‐Raf kinase as mediators of ERK activation by cAMP. Also, in melanocytes, Ras or ERK activation by cAMP is not mediated through protein kinase A activation. Neither the Ras exchange factor, Son of sevenless (SOS), nor the cAMP‐responsive Rap‐1 exchange factor, Epac, participate in the cAMP‐dependent activation of Ras. These findings suggest the existence of a melanocyte‐specific Ras exchange factor directly regulated by cAMP.