Increased
src tyrosine kinase expression and activity has been associated with
colon cancer cell invasion and survival. Several signaling pathways are involved in the oncogenic activation of src during the
adenoma to
carcinoma progression and cellular invasion. In the present study, the synthetic
ether lipid analog ET-18-OMe was shown to promote invasion of HCT-8/S11
colon cancer cells into
collagen type I through the concomitant activation of src by phosphorylation at Tyr416 (5-30 min) in alpha1-integrin immunoprecipitates containing the
integrin binding proteins talin and
paxillin, as well as the phoshorylated and activated forms of
focal adhesion kinase (FAK) at Tyr397 (a FAK
kinase activation signal), Tyr576 and Tyr861. This was associated with the lateral redistribution of alpha1-integrins in focal aggregates and persistent activation of the p130Cas/JNK pathways at 5-30 min, with the subsequent induction and activation of the
matrix metalloproteinases MMP-2 and MMP-9 (2-12 h). These activated molecular scaffolds and signaling cascades were not observed in immunoprecipitates of alpha2- and beta1-integrins, and
tetraspanin CD9, an invasion and
metastasis suppressor linked to
integrins and FAK signaling. Our data demonstrate that the lateral redistribution and clustering of alpha1-integrins results in the recruitment of the FAK/src motility-promoting signaling complex involved in
cancer cell invasion. Disruption of this proinvasive pathway was accomplished by the dominant negative mutant of src (K295R,
kinase dead), src pharmacological inhibitor (PP1) and alpha1-integrin function
blocking antibodies. These findings support the notion that the alpha1-integrin- and src-dependent signalosome is a relevant therapeutic target against
tumor progression in
colon cancer patients.