Adaptor proteins regulate cellular functions in the context of a dynamic membrane interface.

摘要

Accessory proteins regulate critical transmembrane signaling events. Dysregulated transmembrane signaling can result in disorders ranging from the benign, such as mild anemia, to the critical, such as neurofibromatosis. While the mechanisms of signaling regulation are diverse, common themes are present in the cellular context of regulation. Here, we explore two examples of transmembrane signaling regulation: the regulation of adhesive integrin interactions by Src kinase adaptor protein 2 (SKAP2) in the context of erythropoiesis and the regulation of epidermal growth factor receptor (EGFR) signaling by the tumor suppressor protein Merlin in the context of neurofibromatosis type II. Together, these studies emphasize the common context of transmembrane signaling regulation and explore the role of the dynamic membrane environment in this regulation.;Our studies of SKAP2 in erythropoiesis identify a novel genetic cause of hypoproliferative anemia that is associated with decreased adhesive interactions in erythroblastic islands. Our studies support the role of SKAP2 as an integrin signaling modulator in erythropoiesis and highlight the importance of appropriate regulation of transmembrane adhesive interactions.;In the context of tumor suppressor regulation, we found that ligand-bound EGFR is immobilized in the plasma membrane of confluent Merlin-expressing cells in a contact-, actin-, and signaling-dependent manner. Ligand-activated EGFR undergoes receptor-mediated internalization via either clathrin-mediated endocytosis (CME) or non-clathrin endocytosis (NCE). We found that Merlin specifically antagonizes NCE of EGFR independent of cell-cell contact by preventing distribution of the receptor to specific membrane microdomains. In addition, we demonstrated that Merlin-dependent immobilization of EGFR at the surface of confluent cells was signaling-dependent and occurred over a short time (100s), implicating membrane-proximal protein associations and conformational changes in Merlin as key partners in EGFR regulation. These studies of diverse transmembrane signaling events by SKAP2 and Merlin suggest a view of the local membrane environment that is dynamic yet still tightly regulated.