Role of phosphoinositide 3-kinase and the Cbl adaptor protein in coupling the α4β1 integrin to mitogen-activated protein kinase signalling

Cell adhesion mediated by β1 integrin receptors leads to the initiation of intracellular signals that affect cell differentiation and survival. Here we have analysed the mechanism by which the α4β1 integrin activates the mitogen-activated protein kinase pathway in HL60 cells, a myelomonocytic cell line that lacks the expression of focal adhesion kinase. A role for phosphoinositide 3-kinase (PI-3K) in α4 integrin-mediated activation of extracellular signal-regulated protein kinase 2 (ERK2) is suggested by the ability of PI-3K inhibitors and a dominant-negative form of the p85 subunit of PI-3K to block the activation of ERK2 by integrin. Stimulation of α4β1 integrins on HL60 cells also leads to increased tyrosine phosphorylation of the 120 kDa adaptor protein Cbl. PI-3K activity associated with Cbl also increases on the stimulation of α4β1 integrins, although immunodepletion