INTEGRINS CAN COLLABORATE WITH GROWTH-FACTORS FOR PHOSPHORYLATION OF RECEPTOR TYROSINE KINASES AND MAP KINASE ACTIVATION - ROLES OF INTEGRIN AGGREGATION AND OCCUPANCY OF RECEPTORS
S. Miyamoto et al., INTEGRINS CAN COLLABORATE WITH GROWTH-FACTORS FOR PHOSPHORYLATION OF RECEPTOR TYROSINE KINASES AND MAP KINASE ACTIVATION - ROLES OF INTEGRIN AGGREGATION AND OCCUPANCY OF RECEPTORS, The Journal of cell biology, 135(6), 1996, pp. 1633-1642
Integrins mediate cell adhesion, migration, and a variety of signal tr
ansduction events. These integrin actions can overlap or even synergiz
e with those of growth factors. We examined for mechanisms of collabor
ation or synergy between integrins and growth factors involving MAP ki
nases, which regulate many cellular functions. In cooperation with int
egrins, the growth factors EGF, PDGF-BB, and basic FGF each produced a
marked, transient activation of the ERK (extracellular signal-regulat
ed kinase) class of MAP kinase, but only if the integrins were both ag
gregated and occupied by ligand. Transmembrane accumulation of total t
yrosine-phosphorylated proteins, as well as nonsynergistic MAP kinase
activation, could be induced by simple integrin aggregation, whereas e
nhanced transient accumulation of the EGF-receptor substrate eps8 requ
ired integrin aggregation and occupancy, as well as EGF treatment. Eac
h type of growth factor receptor was itself induced to aggregate trans
iently by integrin ligand-coated beads in a process requiring both agg
regation and occupancy of integrin receptors, but not the presence of
growth factor ligand. Synergism was also observed between integrins an
d growth factors for triggering tyrosine phosphorylation of EGF, PDGF,
and FGF receptors. This collaborative response also required both int
egrin aggregation and occupancy. These studies identify mechanisms in
the signal transduction response to integrins and growth factors that
require various combinations of integrin aggregation and ligands for i
ntegrin or growth factor receptors, providing opportunities for collab
oration between these major regulatory systems.