AAPPL1 inhibits cell migration by modulating integrin trafficking and Rac signaling
Diggins, Nicole Lee
Cell migration is vital to numerous biological processes, and is misregulated in pathological processes, such as cancer metastasis. Cell migration is a tightly, spatiotemporally regulated process that requires the coordination of many molecular components. Because adaptor proteins can serve as integrators of various cellular events, they are being increasingly studied as regulators of cell migration. The adaptor protein containing a pleckstrin-homology (PH) domain, phosphotyrosine binding (PTB) domain, and leucine zipper motif 1 (APPL1) is a 709-amino acid endosomal protein that is known to play a role in cell proliferation and survival as well as endosomal trafficking and signaling. However, its function in modulating cell migration is currently poorly understood. In this project, we show that APPL1 expression alters cell migration speeds, but not directionality. APPL1 mediates migration dependent on engagement with Fibronectin and surface level expression of α5β1 integrin, the major Fibronectin receptor. APPL1 alters trafficking patterns of α5β1 integrin, but not αVβ3 integrin, another Fibronectin receptor. Rab5-induced integrin internalization, Rac activation and signaling, and cell migration are hindered by APPL1 interaction with Rab5. These data indicate a role for APPL1 in regulating migration by modulating integrin trafficking as well as Rac activity.