Urokinase-type plasminogen activator stimulates the Ras/extracellular signal-regulated kinase (ERK) signaling pathway and MCF-7 cell migration by a mechanism that requires focal adhesion kinase, Src, and Shc - Rapid dissociation of GRB2/SOS-SHC complex is associated with the transient phosphorylation of ERK in urokinase-treated cells
Dhd. Nguyen et al., Urokinase-type plasminogen activator stimulates the Ras/extracellular signal-regulated kinase (ERK) signaling pathway and MCF-7 cell migration by a mechanism that requires focal adhesion kinase, Src, and Shc - Rapid dissociation of GRB2/SOS-SHC complex is associated with the transient phosphorylation of ERK in urokinase-treated cells, J BIOL CHEM, 275(25), 2000, pp. 19382-19388
Urokinase-type plasminogen activator (uPA) stimulates MCF-7 cell migration
by binding to the UPA receptor and activating the Ras-extracellular signal-
regulated kinase (Ras-ERK) signaling pathway. Studies presented here show t
hat soluble uPA receptor and a peptide derived from the Linker region betwe
en domains 1 and 2 of the uPA receptor also stimulate cellular migration vi
a a mitogen-activated protein kinase/ERK kinase (MEK)-dependent pathway. Si
gnaling proteins that function upstream of Res in uPA-stimulated cells rema
in undefined. To address this problem, we transfected MCF-7 cells to expres
s the noncatalytic carboxylterminal domain of focal adhesion kinase (FAK),
FAK(Y397F), kinase-defective c-Src, or Shc FFF, all of which express domina
nt-negative activity. In each case, ERK phosphorylation and cellular migrat
ion in response to uPA were blocked. Both activities were rescued by co-tra
nsfecting the cells to express constitutively active MEK1, indicating that
FAK, c-Src, and Shc are upstream of MEK. Shc was tyrosine phosphorylated in
uPA-treated cells. The level of phosphorylated Shc was increased within 1
min and remained increased for at least 30 min. Sos co-immunoprecipitated w
ith Shc in cells that were treated with uPA for 1-2.5 min, probably reflect
ing the formation of Shc-Grb2/Sos complex; however, by 10 min, co-immunopre
cipitation of Sos with Shc was no longer observed. Rapid dissociation of So
s from Shc represents a possible mechanism for the transient phosphorylatio
n of ERK in uPA-treated MCF-7 cells.