MERTK interactions with SH2-domain proteins in the retinal pigment epithelium
Open accessAbstract
The receptor tyrosine kinase MERTK plays an essential role in the phagocytic uptake of shed photoreceptor membranes by the retinal pigment epithelium (RPE). A fundamental aspect of signal transduction by receptor tyrosine kinases involves autophosphorylation of tyrosine residues that recruit Src-homology 2 (SH2)-domain proteins to the receptor intracellular domain. The goal of the current study was to evaluate the interactions of human MERTK with SH2-domain proteins present in the RPE. The MERTK intracellular domain was expressed as a 6xHis-fusion protein (6xHis-rMERTK(571-999)), purified and phosphorylated. Ni(2+)-NTA pull downs were performed using 6xHis-rMERTK(571-999) in incubations with recombinant phosphotyrosine-recognition sequences expressed as GST-fusion proteins. In addition, pull downs of native SH2-domain proteins were performed using 6xHis-rMERTK(571-999) and protein homogenates from rat RPE/choroid. For both recombinant and native proteins, western analysis detected MERTK interactions with GRB2, PIK3R1 (P85α), VAV3, and SRC. Immunohistochemical analysis localized each protein to mouse RPE. In cultured RPE-J cells incubated with rod outer segments (OS), siRNA knockdown of Grb2 had no effect on OS binding, but significantly reduced OS uptake. Pik3r1 localized to early phagosomes along with Rab5 and Eea1. Phosphorylation and activation of Src was detected downstream of phagocytosis and Mertk activation. These findings suggest that MERTK signaling in the RPE involves a cohort of SH2-domain proteins with the potential to regulate both cytoskeletal rearrangement and membrane movement. Identification of the SH2-domain signaling partners of MERTK is an important step toward further defining the mechanism of RPE phagocytosis that is central to the function and survival of the retina.
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Although the extent of MERTK's requirement may differ among tissues, it plays a central role, directly or indirectly affecting the regulation of a wide variety of genes including those involved in cytoskeletal rearrangement and phagosome maturation.
“Although the extent of its requirement may differ among different tissues, it nevertheless plays a central role, directly or indirectly affecting the regulation of a wide variety of genes including those involved in cytoskeletal rearrangement and phagosome maturation (Shelby et al., 2013; Penberthy et al., 2017).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Shelby et al., 2013
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The cell biology of the retinal pigment epithelium
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- Authors
- Shelby, S. J., Colwill, K., Dhe-Paganon, S., Pawson, T., & Thompson, D. A.
- Affiliations
- University of Michigan (US)
- Mount Sinai Hospital (CA)
- Corresponding author
- Thompson, Debra A.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-02-04
- Volume
- 8
- Issue
- 2
- Pages
- e53964
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3563642
- OpenAlex
- W2012031383
- Cited by
- 35
- References
- 54
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 2 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 5 · 2013: 2
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Research to Prevent Blindness (EY007003)
- GlaxoSmithKline
- University of Michigan
- Ontario Innovation Trust
- Genome Canada (1097737)
- Wellcome Trust (1097737)
- Ontario Genomics
- Ontario Genomics Institute
- Stiftelsen för Strategisk Forskning
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- National Institutes of Health (1097737, EY007003)
- National Eye Institute (T32 EY13934, P30EY007003, T32EY013934)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60DK020572, P30DK020572)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- MERTK, SH2 domain proteins, retinal pigment epithelium, receptor tyrosine kinase signaling, rod outer segments, Grb2, PIK3R1, Vav3, Src kinase, tyrosine phosphorylation, phagosome, cytoskeletal rearrangement
- MeSH terms
- c-Mer Tyrosine Kinase, Animals, Binding Sites, Choroid, Escherichia coli, Eye Proteins, Gene Expression Regulation, Humans, Phagocytosis, Protein Binding, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Rod Cell Outer Segment, Signal Transduction, src Homology Domains, Phosphotyrosine, src-Family Kinases, Receptor Protein-Tyrosine Kinases, Mice, GRB2 Adaptor Protein, Rats, Proto-Oncogene Proteins c-vav, Retinal Pigment Epithelium, HEK293 Cells, Class Ia Phosphatidylinositol 3-Kinase
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