MERTK (c-mer proto-oncogene tyrosine kinase)

2008-11-01   Amy K Keating , Rachel MA Linger , Doug K Graham 

Department of Pediatrics, University of Colorado at Denver, Health Sciences Center, Aurora, CO, USA




Atlas Image
DNA structure of the MERTK gene aligned with the corresponding functional protein domains. The open ended boxes for exons 1 and 19 indicate untranslated regions which are not depicted here.


The human MERTK gene is located on chromosome 2q14.1 and contains 19 exons. Exons 1-9 encode the extracellular domain, exon 10 encodes the transmembrane domain, and exons 11-19 encode the intracellular domain. Within the extracellular domain, two immunoglobulin (Ig) domains and two fibronectin type III (FNIII) domains are present. The Ig domains are encoded by exons 2-5 and the FNIII domains are encoded by exons 6-9. Within the intracellular region, exons 13-19 encode the tyrosine kinase domain (Gal et al., 2000).


Tissue analysis of MERTK expression has demonstrated a 4.4 kilobase message in a spectrum of tissues including the testis, ovary, prostate, lung, kidney, spleen, placenta, thymus, small intestine, colon, and liver. A larger transcript (approximately 5.5 to 6.5 kilobase message) has been detected in testis and ovary. A potential alternatively spliced transcript is generated by the insertion of a novel exon between exons 7 and exon 8. This alternative transcript may encode a soluble MERTK (Graham et al., 1994).


Atlas Image
The diagram above depicts the domain structure of the Mer receptor tyrosine kinase protein. The conserved sequence within the kinase domain is depicted. The diagram below depicts the domain structure of the ligands, Gas6 and Protein S. Gas6 and Protein S have the same domain structure with the exception of thrombin cleavage sites which are present in the loop region of Protein S but not Gas6. Vitamin-K dependent carboxylation of the Gamma-carboxyglutamic acid (Gla) domain is required for biologic activity of these ligands. The crystal structure of a Gas6/Axl complex suggests that the laminin G-like (LG) domains mediate binding to the Ig-like domains of MERTK.


The MERTK receptor is synthesized as a protein containing 999 amino acids. Although the predicted molecular weight of MERTK is approximately 110 kD, the extracellular domain of MERTK possesses sites for NH2-linked glycosylation and the mature, fully glycosylated form of MERTK is approximately 205 kD (Sather et al., 2007). Depending on the cell type, underglycosylated forms of MERTK protein may also be produced leading to a range in MERTK protein sizes from 160 to 205 kD. The extracellular component of the MERTK receptor encodes two Ig domains (aa 112-186 for domain 1 and aa 197-280 for domain 2) and two FNIII domains (aa 284-378 for domain 1 and 386-478 for domain 2). The two Ig domains and two FNIII domains define MERTK as part of a family of receptor tyrosine kinases (RTKs) which contains only two other members, AXL and Tyro-3. Together, Tyro-3, Axl, and Mer constitute the TAM family of receptor tyrosine kinases (Linger et al., 2008). The extracellular domain of MERTK serves as the ligand binding region for the ligands GAS6 (Chen et al., 1997) and Protein S (Prasad et al., 2006). Specifically, Gas6 has been shown to bind TAM receptors in the immunologlobulin domains (Sasaki et al., 2006).
The intracellular component of the MERTK receptor includes the tyrosine kinase domain (aa 600-848). Within this tyrosine kinase domain is a signature motif, KWIAIES, which is only found in the TAM receptor tyrosine kinases (Graham et al., 1994). Following ligand binding to the extracellular domain, MERTK receptor dimerization and tyrosine autophosphorylation occurs. Three tyrosine residues (Y749, Y753, and Y754) within the activation loop of the kinase domain have been identified as the primary sites of autophosphorylation (Ling et al., 1996). These three residues are also conserved in the same sequence context in Axl and Tyro-3. Another residue within the kinase domain, Y872, is part of consensus GRB2 binding site, YXNX, and the corresponding sequence in murine MERTK has been shown to bind Grb2, recruit and activate PI3K as well as transcriptionally activate NF-kB (Georgescu et al., 1999). Phosphorylation and activation of PLCgamma may occur through direct binding of one of its SH2 domains to endogenous phospho-MERTK (Sen et al., 2007). Similarly, there is evidence that PI3K may interact with MERTK via a SH2 domain (Sen et al., 2007). Finally, VAV1 has been shown to constitutively interact with MERTK, and the release of VAV1 upon ligand-dependent MERTK activation leads to activation of Rho family members (Mahajan et al., 2003).
The extracellular domain of MERTK is also constitutively shed via cleavage due to a metalloproteinase. The resulting soluble MERTK consists of both Ig domains and both FNIII domains, and is believed to function as a decoy receptor for MERTK ligands (Sather et al., 2007).


Within hematopoietic lineages, MERTK is expressed in macrophages, dendritic cells, NK cells, NKT cells, megakaryocytes, and platelets (Graham et al., 1994; Angelillo-Scherrer et al., 2001; Behrens et al., 2003). High levels of MERTK expression are also detected in ovary, prostate, testis, lung, retina, and kidney. Lower levels of Mer are found in heart, brain, and skeletal muscle (Graham et al., 1994). Upregulation or ectopic Mer expression is found in a spectrum of malignant cells (Linger et al., 2008).


MERTK is a transmembrane receptor tyrosine kinase.


The activation of MERTK and downstream signaling via PI3K/Akt, PLCGamma, VAV1, and MAPK/ERK are thought to mediate MERTKs cellular functions in cell survival, proinflammatory cytokine production, and actin reorganization/cell migration. Overexpression or ectopic expression of MERTK has been implicated in oncogenesis (Linger et al., 2008).


The two Ig domains and two FNIII domains are shared with Axl and Tyro-3, the other two members of the TAM RTK family. The protein sequences of TAM receptors are 31-36% identical (52-57% similar) in the extracellular regions. The intracellular domains share 54-59% sequence identity (72-75% similarity) with higher homology in the tyrosine kinase domain (Graham et al., 1995).



Germline mutations in the second exon of MERTK are well characterized and lead to retinitis pigmentosa and retinal dystrophy. The first description of this mutation was in the Royal College of Surgeon (RCS) rat and details a deletion that leads to a frameshift and early translation termination codon, resulting in an aberrant non-functional protein product (DCruz et al., 2000). A similar retinal dystrophy phenotype is found in the merkd mouse, which contains a targeted disruption of the MERTK gene (Duncan et al., 2003). In humans several different mutations that affect the MERTK region have been described in individuals suffering from retinal dystrophy.

Implicated in

Entity name
Retinitis pigmentosa and retinal dystrophy
Retinitis pigementosa is a disorder that affects 1 in 3500 people and stems from loss of functional photoreceptor cells in the retina, and eventual visual loss. Loss of functional MERTK protein leads to ineffective phagocytosis and clearance of apoptotic cells, with resultant buildup of the retinal pigmented epithelium leading to visual loss and is one known genetic cause of retinal dystrophy (Shuster et al., 1990; Gal et al., 2000; Tada et al., 2006; Tschernutter et al., 2006).
Entity name
MERTK and its family members have been implicated in a number of malignant conditions. MERTK is not expressed on the normal lymphocytes but has been found to be expressed in a majority of lymphoblasts from patients with T-cell leukemia, certain subsets of B-cell leukemia, and mantle cell lymphoma (Yeoh et al., 2002; Graham et al., 2006). Forced overexpression of MERTK in a murine model leads to T-cell leukemia and lymphoma (Keating et al., 2006). MERTK has also been associated with a variety of other non-hematologic malignancies including: glioblastoma multiforme (Ling et al., 1995), gastric cancer (Wu et al., 2002), and prostate cancer (Mahajan et al., 2005). MERTK is known to play a role in several oncogenic mechanisms, including angiogenesis, migration and invasion, and cell survival signaling as reviewed in Linger et al (2008).
Entity name
Autoimmune Disease
Animal models that lack functional MERTK protein have macrophages that are unable to appropriately engulf apoptotic cells. This inefficient clearance of dead cells can lead to activation of inflammation and development of autoimmunity (Scott et al., 2001). This mechanism has been suggested for systemic lupus erythematosis, but no human cases have been reported.


Pubmed IDLast YearTitleAuthors
111758532001Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis.Angelillo-Scherrer A et al
128842902003The mer receptor tyrosine kinase: expression and function suggest a role in innate immunity.Behrens EM et al
91608831997Identification of Gas6 as a ligand for Mer, a neural cell adhesion molecule related receptor tyrosine kinase implicated in cellular transformation.Chen J et al
106991882000Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat.D'Cruz PM et al
125564192003An RCS-like retinal dystrophy phenotype in mer knockout mice.Duncan JL et al
110624612000Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa.Gal A et al
98910511999Biological effects of c-Mer receptor tyrosine kinase in hematopoietic cells depend on the Grb2 binding site in the receptor and activation of NF-kappaB.Georgescu MM et al
77840831995Cloning and developmental expression analysis of the murine c-mer tyrosine kinase.Graham DK et al
80863401994Cloning and mRNA expression analysis of a novel human protooncogene, c-mer.Graham DK et al
166755572006Ectopic expression of the proto-oncogene Mer in pediatric T-cell acute lymphoblastic leukemia.Graham DK et al
166521422006Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase.Keating AK et al
85242231995Mitogenic signals and transforming potential of Nyk, a newly identified neural cell adhesion molecule-related receptor tyrosine kinase.Ling L et al
87024771996Identification of the major autophosphorylation sites of Nyk/Mer, an NCAM-related receptor tyrosine kinase.Ling L et al
186200922008TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer.Linger RM et al
162880442005Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox.Mahajan NP et al
169017152006TAM receptor function in the retinal pigment epithelium.Prasad D et al
163620422006Structural basis for Gas6-Axl signalling.Sasaki T et al
170471572007A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation.Sather S et al
113467992001Phagocytosis and clearance of apoptotic cells is mediated by MER.Scott RS et al
170085472007Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NF-kappaB activation in dendritic cells.Sen P et al
16884951990Prognostic factors in childhood T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.Shuster JJ et al
167101672006Screening of the MERTK gene for mutations in Japanese patients with autosomal recessive retinitis pigmentosa.Tada A et al
167142632006Clinical characterisation of a family with retinal dystrophy caused by mutation in the Mertk gene.Tschernutter M et al
121689032002Clinical significance of AXL kinase family in gastric cancer.Wu CW et al
120868722002Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling.Yeoh EJ et al

Other Information

Locus ID:

NCBI: 10461
MIM: 604705
HGNC: 7027
Ensembl: ENSG00000153208


dbSNP: 10461
ClinVar: 10461
TCGA: ENSG00000153208


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cell surface interactions at the vascular wallREACTOMER-HSA-202733

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
186200922008TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer.248
229424262012Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction.155
170471572007A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation.125
170056882006Tyro3 family-mediated cell entry of Ebola and Marburg viruses.121
209784722010Tubby and tubby-like protein 1 are new MerTK ligands for phagocytosis.71
250749262014Receptor tyrosine kinases, TYRO3, AXL, and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation.64
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
228903232013Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer.62
180396602008Autophosphorylation docking site Tyr-867 in Mer receptor tyrosine kinase allows for dissociation of multiple signaling pathways for phagocytosis of apoptotic cells and down-modulation of lipopolysaccharide-inducible NF-kappaB transcriptional activation.61
235854772013MERTK receptor tyrosine kinase is a therapeutic target in melanoma.60


Amy K Keating ; Rachel MA Linger ; Doug K Graham

MERTK (c-mer proto-oncogene tyrosine kinase)

Atlas Genet Cytogenet Oncol Haematol. 2008-11-01

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