Phosphoprotein enriched in astrocytes 15 kDa (PEA-15) reprograms growth factor signaling by inhibiting threonine phosphorylation of fibroblast receptor substrate 2alpha. Academic Article uri icon

abstract

  • Changes in cellular expression of phosphoprotein enriched in astrocytes of 15 kDa (PEA-15) are linked to insulin resistance, tumor cell invasion, and cellular senescence; these changes alter the activation of the extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein (MAP) kinase pathway. Here, we define the mechanism whereby increased PEA-15 expression promotes and sustains ERK1/2 activation. PEA-15 binding prevented ERK1/2 membrane recruitment and threonine phosphorylation of fibroblast receptor substrate 2alpha (FRS2alpha), a key link in fibroblast growth factor (FGF) receptor activation of ERK1/2. This reduced threonine phosphorylation led to increased FGF-induced tyrosine phosphorylation of FRS2alpha, thereby enhancing downstream signaling. Conversely, short hairpin RNA-mediated depletion of endogenous PEA-15 led to reduced FRS2alpha tyrosine phosphorylation. Thus, PEA-15 interrupts a negative feedback loop that terminates growth factor receptor signaling downstream of FRS2alpha. This is the dominant mechanism by which PEA-15 activates ERK1/2 because genetic deletion of FRS2alpha blocked the capacity of PEA-15 to activate the MAP kinase pathway. Thus, PEA-15 prevents ERK1/2 localization to the plasma membrane, thereby inhibiting ERK1/2-dependent threonine phosphorylation of FRS2alpha to promote activation of the ERK1/2 MAP kinase pathway.

published proceedings

  • Mol Biol Cell

author list (cited authors)

  • Haling, J. R., Wang, F., & Ginsberg, M. H.

citation count

  • 7

complete list of authors

  • Haling, Jacob R||Wang, Fen||Ginsberg, Mark H

editor list (cited editors)

  • Brugge, J.

publication date

  • February 2010