Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors.

Abstract

Abstract. Integrins mediate cell adhesion, migration, and a variety of signal transduction events. These integrin actions can overlap or even synergize with those of growth factors. We examined for mechanisms of collaboration or synergy between integrins and growth factors involving MAP kinases, which regulate many cellular functions. In cooperation with integrins, the growth factors EGF, PDGF-BB, and basic FGF each produced a marked, transient activation of the ERK (extracellular signal-regulated kinase) class of MAP kinase, but only if the integrins were both aggregated and occupied by ligand. Transmembrane accumulation of total tyrosine-phosphorylated proteins, as well as nonsynergistic MAP kinase activation, could be induced by simple integrin aggregation, whereas enhanced transient accumulation of the EGF-receptor substrate eps8 required integrin aggregation and occupancy, as well as EGF treatment. Each type of growth factor receptor was itself induced to aggregate transiently by integrin ligandcoated beads in a process requiring both aggregation and occupancy of integrin receptors, but not the presence of growth factor ligand. Synergism was also observed between integrins and growth factors for triggering tyrosine phosphorylation of EGF, PDGF, and FGF receptors. This collaborative response also required both integrin 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 integrin or growth factor receptors, providing opportunities for collaboration between these major regulatory systems. INTEGRINS mediate a wide variety of biological processes by functioning as receptors and transmembrane transducers in cell adhesion, migration, and signal transduction events (Hynes, 1992;Gumbiner, 1993;Clark and Brugge, 1995;Schwartz et al., 1995;Yamada and Miyamoto, 1995;Rosales et al., 1995;Richardson and Parsons, 1995;Parsons, 1996;Ruoslahti, 1996;Gumbiner, 1996). For example, interactions of ligands with integrins can stimulate a variety of signaling events including tyrosine phosphorylation (reviewed by Schwartz et al

Ascites induces modulation of α6β1 integrin and urokinase plasminogen activator receptor expression and associated functions in ovarian carcinoma

“…uPA/uPAR interaction with b1 integrin has been shown to activate Erk pathway (Ahmed et al, 2003a) and disruption of this interaction can result in loss of adhesion and tumour progression in nude mice (van der Pluijm et al, 2001). The uPAR -integrin interaction is crucial as many integrin receptors activate intracellular signal pathways to fully activate cell survival and proliferation pathways (Miyamoto et al, 1996). Recently, we have shown that the cytoplasmic domain of avb6 integrin interacts with Erk and that interaction is essential to maintain tumour growth in mice (Ahmed et al, 2002a).…”

Mechanoregulation of gene expression in fibroblasts

“…RTK pathway may not function in isolation; direct associations of RTKs and integrins have been identified. Integrin receptor occupancy and clustering may be required for RTK phosphorylation and activation (Miyamoto et al, 1996). CD44 is transmembrane protein that serves as an adhesion molecule for hyaluronan (HA), an ECM component (Aruffo et al, 1990;Nagano and Saya, 2004).…”

Integrins in regulation of tissue development and function

“…Fourthly, integrin-mediated adhesion can cluster and transactivate several receptor tyrosine kinases (RTKs) including PDGFR and EGFR [23,24], Ron [25], Met [26], and VEGFR [27] (Figure 2D). As integrinmediated transactivation of RTKs can occur in the absence of cognate growth factor, this phenomenon may in fact explain some of the signalling events previously attributed more directly to integrin signalling.…”