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 alpha IIb beta 3 in platelets have been investigated intensively. In contrast, activation via integrin alpha 6 beta 1 is less well studied. Here, we provide the first biochemical evidence that integrins alpha 6 beta 1 and alpha IIb beta 3 of platelets are associated with different membrane proteins. We also demonstrate that platelets activated by integrin alpha 6 beta 1 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 alpha 6 beta 1 are different from those activated by integrin alpha IIb beta 3 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 alpha 6 beta 1 activation is highly dependent on PI3 kinase (PI3K) but less dependent on Src kinase. Suppression of PI3K activity in integrin alpha 6 beta 1 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 alpha 6 beta 1 than in those activated by integrin alpha IIb beta 3. Taken together, this study demonstrates that the signals induced by integrin alpha 6 beta 1 modulate at the level of PI3K and Cdc42 activity to allow platelets to actively form filopodia.