MERTK

Official Full Name

MER proto-oncogene, tyrosine kinase

Organism

Homo sapiens

GeneID

10461

Background

This gene is a member of the MER/AXL/TYRO3 receptor kinase family and encodes a transmembrane protein with two fibronectin type-III domains, two Ig-like C2-type (immunoglobulin-like) domains, and one tyrosine kinase domain. Mutations in this gene have been associated with disruption of the retinal pigment epithelium (RPE) phagocytosis pathway and onset of autosomal recessive retinitis pigmentosa (RP). [provided by RefSeq, Jul 2008]

Synonyms

MER; RP38; c-Eyk; c-mer; Tyro12;

Bio Chemical Class

Kinase

Protein Sequence

MGPAPLPLLLGLFLPALWRRAITEAREEAKPYPLFPGPFPGSLQTDHTPLLSLPHASGYQPALMFSPTQPGRPHTGNVAIPQVTSVESKPLPPLAFKHTVGHIILSEHKGVKFNCSISVPNIYQDTTISWWKDGKELLGAHHAITQFYPDDEVTAIIASFSITSVQRSDNGSYICKMKINNEEIVSDPIYIEVQGLPHFTKQPESMNVTRNTAFNLTCQAVGPPEPVNIFWVQNSSRVNEQPEKSPSVLTVPGLTEMAVFSCEAHNDKGLTVSKGVQINIKAIPSPPTEVSIRNSTAHSILISWVPGFDGYSPFRNCSIQVKEADPLSNGSVMIFNTSALPHLYQIKQLQALANYSIGVSCMNEIGWSAVSPWILASTTEGAPSVAPLNVTVFLNESSDNVDIRWMKPPTKQQDGELVGYRISHVWQSAGISKELLEEVGQNGSRARISVQVHNATCTVRIAAVTRGGVGPFSDPVKIFIPAHGWVDYAPSSTPAPGNADPVLIIFGCFCGFILIGLILYISLAIRKRVQETKFGNAFTEEDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNKLEDVVIDRNLLILGKILGEGEFGSVMEGNLKQEDGTSLKVAVKTMKLDNSSQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMSSQGIPKPMVILPFMKYGDLHTYLLYSRLETGPKHIPLQTLLKFMVDIALGMEYLSNRNFLHRDLAARNCMLRDDMTVCVADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRVYTSKSDVWAFGVTMWEIATRGMTPYPGVQNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTDPLDRPTFSVLRLQLEKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPDSIIASCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAEKNSVLPGERLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM

Open

Disease

Acute myeloid leukaemia, Alzheimer disease, Brain cancer, Mature B-cell lymphoma, Myelodysplastic syndrome, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

7 +

Discontinued Drug

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Detailed Information

The proto-oncogene tyrosine protein kinase MER is an enzyme encoded by the MERTK gene in humans. This gene is a member of the TYRO3 / AXL / MER (TAM) receptor kinase family and encodes two fibronectin type III domains, two Ig-like C2 (immunoglobulin-like) domains and one tyrosine kinase domain of transmembrane proteins. When the MERTK gene is defective, it shows that the retinal pigment epithelium (RPE) phagocytic photoreceptor loses its function of the disc membrane, which eventually leads to the loss of photoreceptors. The protein expressed by the MERTK gene is a transmembrane receptor tyrosine kinase, which is expressed in many tissues of the whole body and participates in various physiological functions. It is also expressed in RPE and functions to participate in the phagocytosis of the outer disc membrane of photoreceptors. Mutations in this gene are associated with disruption of the retinal pigment epithelial (RPE) phagocytic pathway and the onset of autosomal recessive retinitis pigmentosa (RP).

The common ligand for the Mer receptor tyrosine kinase subfamily (Tyro3, Axl and MERTK) is Gas 6 and protein s (abbreviated as PS). MERTK binds to the ligands Gas6 and PS, and its conformation changes to form homo- or heterodimers. Phosphorylation of intracellular tyrosine residues activates the tyrosine protein kinase activity of the receptor itself, catalyzing downstream molecule, which acts as a signal transduction. It can regulate spermatogenesis, inhibit apoptosis of neuronal cells, participate in cell adhesion and phosphorylation of protein amino acids.

MERTK and RP

The RCS (royal college of Surgeons) rat is a naturally mutated autosomal recessive retinitis oigmmentosa (ARRP). It was found that MERTK knockout mice have retinal changes similar to those of RCS rats. Gene sequence analysis of RCS rats revealed that the gene encoding RCSMERTK tyrosine kinase was clearly lost at the 5' end, and this loss included the upstream sequence of the second coding exon of MERTK, resulting in a shortening of a 20 amino acid polypeptide. Therefore, RCS rats are indeed associated with mutations in the MERTK gene.

Studies have shown that MERTK knockout mice cause loss of photoreceptors due to loss of RPE phagocytosis, which in turn leads to changes in cells in the retina. The MERTK signaling pathway plays an important role in the normal presence of photoreceptors. MERTK is expressed at the microvilli of the top of the RPE, that is, the site where the detached photoreceptor disk membrane is phagocytized, and MERTK participates in the process of RPE phagocytizing the outer disc membrane of the photoreceptor. Studies have shown that the viral vector carrying the MERTK gene transfected into the RPE of RCS rats can partially restore the phagocytic function of RPE and rescue the photoreceptors.

Figure 1. The PS receptor MERTK acts as an inhibitory receptor to promote homeostasis and tissue tolerance. (Birge, R. B., et al. 2016)

MERTK and Other Diseases

MERTK is a class of proteins on the surface of macrophages that regulate inflammation repair and effector cell proliferation. Phagocytosis can occur by binding to phosphatidylserine which is reversed on the surface of apoptotic cells. In addition, macrophages are also able to inhibit the NF-KB signaling pathway. The inflammatory injury repair process relies on specific regulatory factors (SPM), which function by regulating binding to cell surface receptors. Studies have shown that MERTK signals can promote the synthesis of SPM. Cai et al. induced peritonitis in mice, after which they compared the differences in inflammatory repair between wild-type mice and MERTK KO mice. The results showed that the inflammatory repair ability of the mutant mice was significantly lower than that of the wild type, and the clearance ability of the apoptotic cells was also significantly weaker. Further studies found that MERTK on the surface of macrophages in mutant mice was no longer affected by metalloproteinases, and in vitro inflammatory repair ability remained stable.

References:

Cai, B. , Thorp, E. B. , Doran, A. C. , Subramanian, M. , Sansbury, B. E. , & Lin, C. S. , et al. (2016). MERTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation. Proc Natl Acad Sci U S A, 113(23), 6526-6531.
Yan, D. , Wang, X. , Frye, S. V. , Earp, S. H. , Deryckere, D. , & Graham, D. K. . (2017). Abstract 1082: MERTK promotes resistance to irreversible egfr tkis by activation of the pi3k-akt pathway in nsclcs expressing wild-type egfr. Cancer Research,77(13 Supplement), 1082-1082.
Birge, R. B. , Boeltz, S. , Kumar, S. , Carlson, J. , Wanderley, J. , & Calianese, D. , et al. (2016). Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death and Differentiation.

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