title: The endosomal adaptor protein APPL1 impairs the turnover of leading edge adhesions to regulate cell migration.
abstract: Cell migration is a complex process that requires the integration of signaling events that occur in distinct locations within the cell. Adaptor proteins, which can localize to different subcellular compartments, where they bring together key signaling proteins, are emerging as attractive candidates for controlling spatially coordinated processes. However, their function in regulating cell migration is not well understood. In this study, we demonstrate a novel role for the adaptor protein containing a pleckstrin-homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (APPL1) in regulating cell migration. APPL1 impairs migration by hindering the turnover of adhesions at the leading edge of cells. The mechanism by which APPL1 regulates migration and adhesion dynamics is by inhibiting the activity of the serine/threonine kinase Akt at the cell edge and within adhesions. In addition, APPL1 significantly decreases the tyrosine phosphorylation of Akt by the nonreceptor tyrosine kinase Src, which is critical for Akt-mediated cell migration. Thus, our results demonstrate an important new function for APPL1 in regulating cell migration and adhesion turnover through a mechanism that depends on Src and Akt. Moreover, our data further underscore the importance of adaptor proteins in modulating the flow of information through signaling pathways.
authors.affiliation: Department of Biological Sciences and Vanderbilt Kennedy Center for Research on Human Development, Nashville, TN 37235, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Broussard
authors.forename: Wan-hsin
authors.initials: WH
authors.lastname: Lin
authors.forename: Devi
authors.initials: D
authors.lastname: Majumdar
authors.forename: Bridget
authors.initials: B
authors.lastname: Anderson
authors.forename: Brady
authors.initials: B
authors.lastname: Eason
authors.forename: Claire M
authors.initials: CM
authors.lastname: Brown
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Webb
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D006801:Humans; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D034741:RNA, Small Interfering; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt