MERTK-mediated Signaling in the Retinal Pigment Epithelium: Insights into the Mechanism of RPE Phagocytosis.

RPE Phagocytosis;MERTK;Regulation of RPE Phagocytosis;Biological Chemistry;Science;Biological Chemistry

Shelby, Shameka J.Margolis, Benjamin L. ;

University of Michigan

关键词: RPE Phagocytosis;    MERTK;    Regulation of RPE Phagocytosis;    Biological Chemistry;    Science;    Biological Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/96052/sdarisaw_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

A key function of the retinal pigment epithelium (RPE) is the phagocytic uptake of outer segment (OS) membranes shed from the distal tips of the photoreceptor cells in diurnal rhythm.The shedding and removal of effete OS membranes is essential for the normal function and renewal of the light-absorbing rod and cone photoreceptor cells.Mutations affecting the mechanism of RPE phagocytosis can result in inherited retinal degeneration. In the dystrophic Royal College of Surgeons (RCS) rat, a loss of function mutation in the gene encoding the receptor tyrosine kinase MERTK disrupts phagocytic uptake, but not binding, of shed OS membranes. As a consequence, a debris field forms in the subretinal space, blocking the supply of oxygen and nutrients to the photoreceptors resulting in retinal degeneration and vision loss.Activation of MERTK results in receptor autophosphorylation and interaction with a diverse array of signaling proteins. Using studies of recombinant protein interactions, this thesis shows that MERTK interacts with multiple SH2-domain proteins in the RPE, including effectors of Rho family GTPases that regulate cytoskeletal reorganization needed for phagocytic uptake. Signaling downstream of MERTK also results in tyrosine phosphorylation of cellular protein substrates. During peak phagocytosis by the RPE, MERTK activation was shown to stimulate the tyrosine phosphorylation of RabGDIα, an effector of the Rab family of small GTPases that contribute to membrane localization. In addition, RabGDIα was shown to interact with Rab5 that is involved in early phagosome formation. These results suggest a direct role of MERTK in the regulation of membrane trafficking and cargo sorting in the RPE. The present findings extend our understanding of the role of MERTK in RPE phagocytosis.Identification of signaling partners and downstream effects of MERTK activation suggests multiple links to cytoskeletal rearrangement as well as a novel role in regulating phagosome trafficking in the RPE.Insights into the RPE phagocytic mechanism will further our understanding of the cell biology underlying the visual process and provide a foundation for studies aimed at therapeutic intervention in diseases of the retina.