The heparin-binding growth factor, MK, promoting tumorigenesis and survival was found to associate with alpha 6 beta 1 integrins. We showed for the first time that MK interacted with TSPAN1 and facilitated the association between TSPAN1 and integrin alpha 6 beta 1 proteins in head and neck squamous cell carcinoma (HNSCC) cells. We found that MK mediated an integrin-dependent tyrosine phosphorylation of FAK and activation of paxillin and Stat1 alpha pathways. AS result, downstream target genes implicated in cell migration and invasiveness (e.g. MMP-2 and MMP-26) were overexpressed. We observed that RNAi silencing of the critical signaling intermediates led to decrease of MK-induced migration/invasiveness of HNSCC cells. The major finding of this study is a novel MK-triggered signaling mechanism implicated in migration and invasiveness of HNSCC cells. (C) 2008 Elsevier Inc. All rights reserved.