The integrin α6β1 modulation of PI3K and Cdc42 activities induces dynamic filopodium formation in human platelets

Platelets are an ideal model for studying a rapid morphological change in response to various signal transduction systems. Morphological changes via the activation of integrin αIIbβ3 in platelets have been investigated intensively. In contrast, activation via integrin α6β1 is less well studied. Here, we provide the first biochemical evidence that integrins α6β1 and αIIbβ3 of platelets are associated with different membrane proteins. We also demonstrate that platelets activated by integrin α6β1 show dynamic change by actively forming filopodia and never fully spreading over a period of more than an hour. In addition, platelets activated by integrin α6β1 are different from those activated by integrin αIIbβ3 in terms of cell-substrate contact and in their distribution pattern of actin, Arp2/3 and various phosphotyrosine proteins. The morphological appearance of platelets produced through integrin α6β1 activation is highly dependent on PI3 kinase (PI3K) but less dependent on Src kinase. Suppression of PI3K activity in integrin α6β1 activated platelets induces an increase in Cdc42 activity and more filopodium formation. However, both Cdc42 and PI3K activity are higher in platelets activated by integrin α6β1 than in those activated by integrin αIIbβ3. Taken together, this study demonstrates that the signals induced by integrin α6β1 modulate at the level of PI3K and Cdc42 activity to allow platelets to actively form filopodia.