Format

Send to

Choose Destination
Exp Eye Res. 2015 Nov;140:28-40. doi: 10.1016/j.exer.2015.08.006. Epub 2015 Aug 15.

MERTK signaling in the retinal pigment epithelium regulates the tyrosine phosphorylation of GDP dissociation inhibitor alpha from the GDI/CHM family of RAB GTPase effectors.

Author information

1
Department of Biological Chemistry, University of Michigan Medical School, 1150 W. Medical Center Dr., Ann Arbor, MI 48109, USA; Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, 1000 Wall St., Ann Arbor, MI 48105, USA.
2
Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, 1000 Wall St., Ann Arbor, MI 48105, USA.
3
Department of Biological Chemistry, University of Michigan Medical School, 1150 W. Medical Center Dr., Ann Arbor, MI 48109, USA.
4
Department of Biological Chemistry, University of Michigan Medical School, 1150 W. Medical Center Dr., Ann Arbor, MI 48109, USA; Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, 1000 Wall St., Ann Arbor, MI 48105, USA. Electronic address: dathom@umich.edu.

Abstract

Photoreceptor outer segments (OS) in the vertebrate retina undergo a process of continual renewal involving shedding of disc membranes that are cleared by phagocytic uptake into the retinal pigment epithelium (RPE). In dystrophic Royal College of Surgeons (RCS) rats, OS phagocytosis is blocked by a mutation in the gene encoding the receptor tyrosine kinase MERTK. To identify proteins tyrosine-phosphorylated downstream of MERTK in the RPE, MALDI-mass spectrometry with peptide-mass fingerprinting was used in comparative studies of RCS congenic and dystrophic rats. At times corresponding to peak phagocytic activity, the RAB GTPase effector GDP dissociation inhibitor alpha (GDI1) was found to undergo tyrosine phosphorylation only in congenic rats. In cryosections of native RPE/choroid, GDI1 colocalized with MERTK and the intracellular tyrosine-kinase SRC. In cultured RPE-J cells, and in transfected heterologous cells, MERTK stimulated SRC-mediated tyrosine phosphorylation of GDI1. In OS-fed RPE-J cells, GDI1 colocalized with MERTK and SRC on apparent phagosomes located near the apical membrane. In addition, both GDI1 and RAB5, a regulator of vesicular transport, colocalized with ingested OS. Taken together, these findings identify a novel role of MERTK signaling in membrane trafficking in the RPE that is likely to subserve mechanisms of phagosome formation.

KEYWORDS:

Phagocytosis; RAB GTPase; Retinal dystrophy; Retinal pigment epithelium; Tyrosine phosphorylation

PMID:
26283020
PMCID:
PMC4624558
DOI:
10.1016/j.exer.2015.08.006
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center