Melanoma cell migration to type IV collagen requires activation of NF-jB

Chemotaxis is the consequence of environmental factors engaging their receptors to initiate signaling cascades. However, the biochemical mechanisms controlling this phenomenon are not clear. We employed an in vitro modified Boyden 48-well chemotaxis migration system to characterize the role of signal transducers in type IV collagen (CIV) induced A2058 human melanoma cell migration. Using specific pharmacological inhibitors and a series of dominant-negative and constitutively active signaling proteins, we show that Ras and Rac GTPases, PI-3K, and PKC participate in cell migration mediated by b1 integrins. Collagen also induces a timedependent degradation of IjB-a and an increase in nuclear translocation of NF-jB which is dependent on PKC pathway. More importantly, collagen-stimulated melanoma cell migration directly correlated with an increase in NF-jB transactivation. Furthermore, CIV induced an increase in b1 integrin mRNA levels. Specific NF-jB inhibitors Helenalin and SN-50 inhibited melanoma cell migration to collagen, indicating a novel requirement for NF-jB transactivation in cell chemotaxis mediated by b1 integrin signals. These results describe signal transduction events that are initiated by type IV collagen through b1 integrins and demonstrate an important role for NF-jB in regulating melanoma chemotaxis. Oncogene (2003) 22, 98–108. doi:10.1038/sj.onc.1206059