L1 can function as a trans-heterophilic ligand for multiple members of the integrin superfamily. It binds multiple integrins including alphavbeta3, alphavbeta1, alpha5beta1, alphaIIbbeta3 and alpha9beta 1. The RGD motif in the sixth Ig domain and the third FnIII repeat of L1 are important for these interactions, which serves to strengthen the adhesion of the neuron to the extracellular matrix.
L1 and beta1 integrins association activates a common intracellular signaling pathway. This pathway involves the sequential activation of the tyrosine kinase c-Src, PI3 kinase, Vav2 guanine nucleotide exchange factor, Rac1 GTPase, PAK1, MEK, and the MAP kinases ERK1/2, which is essential for L1 induced neurite outgrowth and cell motility.