Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity

Nguyen, Khanh Q.; Tsou, Wen I.; Calarese, D.A.; Kimani, Stanley; Singh, Sukhwinder; Hsieh, Shelly; Liu, Yongzhang; Lü, Bin; Yu, Wu; Garforth, S.; Almo, S.C.; Kotenko, Sergei V.; Birge, Raymond B.

doi:10.1074/jbc.m114.570838

Cited by 80 publications

(84 citation statements)

References 65 publications

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“…4 -6), GAS6 acquires the capability to induce stronger activation of MER; therefore, MER may act as a preferred receptor for GAS6 opsoninzed to PS. This hypothesis is also supported by studies of Nguyen et al (50) demonstrating that ACs only enhance GAS6 induced receptor autophosphorylation in cells expressing MER, but not AXL. This raises an interesting possibility that following PS opsonization, GAS6 switches from preferential AXL binding to MER binding, and, taken further, that MER will function mainly as an efferocytosis receptor that interacts with the surface of ACs, while AXL interacts with un-opsonized GAS6 to stimulate conventional RTK signaling.…”

Section: Discussionsupporting

confidence: 74%

Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

Tsou

Nguyen²,

Calarese³

et al. 2014

Journal of Biological Chemistry

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191

203

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Background:The mechanisms by which ligands activate TAM receptors (TYRO3, AXL, and MER) are not well understood. Results:We created a series of TAM reporter cell lines and interrogated ligand-inducible TAM activation. Conclusion: TAMs are differentially activated by GAS6 and protein S and have distinct requirements for phosphatidylserine. Significance: Results reveal molecular mechanisms and rationale for non-overlapping functions of TAMs.

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Section: Discussionsupporting

confidence: 74%

Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

Tsou

Nguyen²,

Calarese³

et al. 2014

Journal of Biological Chemistry

Self Cite

191

203

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“…MERTK protocol. IHC staining for MERTK was conducted as described (69). Briefly, we followed the same primary antibody protocol as described above, but to increase the sensitivity of MERTK staining we used a biotinylated secondary antibody (goat anti-rabbit IgG; Boster Biotechnology), followed by peroxidase-conjugated streptavidin (SABC; SA1022; Boster Biotechnology).…”

Section: Secondary In Vivo Kinase Screenmentioning

confidence: 99%

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Faltermeier

Drake

Clark

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention.kinases | metastasis | prostate cancer | bone metastasis M etastatic prostate cancer is responsible for the deaths of ∼30,000 men in the United States each year (1, 2). Ninety percent of patients develop bone metastases, and other major sites of metastases include lymph nodes, liver, adrenal glands, and lung (3). First-line treatments for metastatic disease are androgen deprivation therapies that block androgen synthesis or signaling through the androgen receptor (AR) (2). Inevitably, metastatic prostate cancer becomes resistant to androgen blockade. Second-line treatments such as chemotherapy (docetaxel, cabazitaxel) and radiation only extend survival 2-4 mo (4, 5).Identifying new therapeutic targets for metastatic prostate cancer has proven difficult. Exome and whole-genome sequencing of human metastatic prostate cancer tissues have found frequent mutations and/or chromosomal aberrations in numerous genes, including AR, TP53, PTEN, BRCA2, and MYC (6-11). The precise functional contribution of these genes to prostate cancer metastasis remains unknown. Genomic and phosphoproteomic analyses have also revealed that metastatic prostate cancer is molecularly heterogeneous, which has complicated the search for common therapeutic targets (12). Few murine models of prostate cancer develop metastases. Mice having prostate-specific homozygous deletions in SMAD4 and PTEN or expression of mutant KRAS develop metastases in visceral organs but rarely in bone (13-15).Targeting genetically altered constitutively active protein kinases such as BCR-ABL in chronic myelogenous leukemia and BRAF V600E in melanoma has led to dramat...

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“…44 Studies have implicated Mertk to not only be highly elevated in human breast carcinoma samples, but also mediate efferocytosis in macrophages and advance tumor progression through the inhibition of immune checkpoints. 45 In this experiment, MCP-1 depletion resulted in a reduction in both Mertk and CD64 mRNA expression in the mammary gland, and also CD64 mRNA expression in the tumor tissue. These results are consistent with a very recent study in which Fang et al, demonstrated a reduction in the recruitment of macrophages to the tumor microenvironment with targeted MCP-1 gene silencing in a model of TNBC cancer.…”

Section: Discussionmentioning

confidence: 95%

Loss of monocyte chemoattractant protein-1 expression delays mammary tumorigenesis and reduces localized inflammation in the C3(1)/SV40Tag triple negative breast cancer model

Cranford

Velázquez

Enos

et al. 2017

Cancer Biology & Therapy

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Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a major modulator in the progression of mammary tumorigenesis, largely due to its ability to recruit macrophages to the tumor microenvironment. Macrophages are key mediators in the connection between inflammation and cancer progression and have been shown to play an important role in tumorigenesis. Thus, MCP-1 may be a potential therapeutic target in inflammatory and difficult-to-treat cancers such as triple negative breast cancer (TNBC). We examined the effect of MCP-1 depletion on mammary tumorigenesis in a model of TNBC. Tumor measurements were conducted weekly (until 22 weeks of age) and at sacrifice (23 weeks of age) in female C3(1)/SV40Tag and C3(1)/SV40Tag MCP-1 deficient mice to determine tumor numbers and tumorvolumes. Histopathological scoring was performed at 12 weeks of age and 23 weeks of age. Gene expression of macrophage markers and inflammatory mediators were measured in the mammary gland and tumor microenvironment at sacrifice. As expected, MCP-1 depletion resulted in decreased tumorigenesis, indicated by reduced primary tumor volume and multiplicity, and a delay in tumor progression represented by histopathological scoring (12 weeks of age). Deficiency in MCP-1 significantly downregulated expression of macrophage markers in the mammary gland (Mertk and CD64) and the tumor microenvironment (CD64), and also reduced expression of inflammatory cytokines in the mammary gland (TNFa and IL-1b) and the tumor microenvironment (IL-6). These data support the hypothesis that MCP-1 expression contributes to increased tumorigenesis in a model of TNBC via recruitment of macrophages and subsequent increase in inflammatory mediators.

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Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity

Cited by 80 publications

References 65 publications

Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Loss of monocyte chemoattractant protein-1 expression delays mammary tumorigenesis and reduces localized inflammation in the C3(1)/SV40Tag triple negative breast cancer model

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