Overexpression of MERTK receptor tyrosine kinase in epithelial cancer cells drives efferocytosis in a gain-of-function capacity

Khanh Quynh N Nguyen, Wen I. Tsou, Daniel A. Calarese, Stanley G. Kimani, Sukhwinder Singh, Shelly Hsieh, Yongzhang Liu, Bin Lu, Yi Wu, Scott J. Garforth, Steven C. Almo, Sergei V. Kotenko, Raymond B. Birge

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

MERTK, a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases, has complex and diverse roles in cell biology. On the one hand, knock-out of MERTK results in agedependent autoimmunity characterized by failure of apoptotic cell clearance, while on the other, MERTK overexpression in cancer drives classical oncogene pathways leading to cell transformation. To better understand the interplay between cell transformation and efferocytosis, we stably expressed MERTK in human MCF10A cells, a non-tumorigenic breast epithelial cell line devoid of endogenous MERTK. While stable expression of MERTK in MCF10A resulted in enhanced motility and AKTmediated chemoprotection, MERTK-10A cells did not form stable colonies in soft agar, or enhance proliferation compared with parental MCF10A cells. Concomitant to chemoresistance, MERTK also stimulated efferocytosis in a gain-of-function capacity. However, unlike AXL, MERTK activation was highly dependent on apoptotic cells, suggestingMERTKmay preferentially interface with phosphatidylserine. Consistent with this idea, knockdown ofMERTKin breast cancer cellsMDA-MB231 reduced efferocytosis, while transient or stable expression of MERTK stimulated apoptotic cell clearance in all cell lines tested. Moreover, human breast cancer cells with higher endogenous MERTK showed higher levels of efferocytosis that could be blocked by solubleTAMreceptors. Finally, through MERTK, apoptotic cells induced PD-L1 expression, an immune checkpoint blockade, suggesting that cancer cells may adopt MERTKdriven efferocytosis as an immune suppression mechanism for their advantage. These data collectively identify MERTK as a significant link between cancer progression and efferocytosis, and a potentially unrealized tumor-promoting event when MERTK is overexpressed in epithelial cells.

Original languageEnglish (US)
Pages (from-to)25737-25749
Number of pages13
JournalJournal of Biological Chemistry
Volume289
Issue number37
DOIs
StatePublished - Sep 12 2014

Fingerprint

Receptor Protein-Tyrosine Kinases
Epithelial Cells
Cells
Neoplasms
Cytology
Phosphatidylserines
Agar
Breast Neoplasms
Tumors
Cell Line
Chemical activation
Autoimmunity
Oncogenes
Cell Biology
Breast

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Nguyen, K. Q. N., Tsou, W. I., Calarese, D. A., Kimani, S. G., Singh, S., Hsieh, S., ... Birge, R. B. (2014). Overexpression of MERTK receptor tyrosine kinase in epithelial cancer cells drives efferocytosis in a gain-of-function capacity. Journal of Biological Chemistry, 289(37), 25737-25749. https://doi.org/10.1074/jbc.M114.570838

Overexpression of MERTK receptor tyrosine kinase in epithelial cancer cells drives efferocytosis in a gain-of-function capacity. / Nguyen, Khanh Quynh N; Tsou, Wen I.; Calarese, Daniel A.; Kimani, Stanley G.; Singh, Sukhwinder; Hsieh, Shelly; Liu, Yongzhang; Lu, Bin; Wu, Yi; Garforth, Scott J.; Almo, Steven C.; Kotenko, Sergei V.; Birge, Raymond B.

In: Journal of Biological Chemistry, Vol. 289, No. 37, 12.09.2014, p. 25737-25749.

Research output: Contribution to journalArticle

Nguyen, KQN, Tsou, WI, Calarese, DA, Kimani, SG, Singh, S, Hsieh, S, Liu, Y, Lu, B, Wu, Y, Garforth, SJ, Almo, SC, Kotenko, SV & Birge, RB 2014, 'Overexpression of MERTK receptor tyrosine kinase in epithelial cancer cells drives efferocytosis in a gain-of-function capacity', Journal of Biological Chemistry, vol. 289, no. 37, pp. 25737-25749. https://doi.org/10.1074/jbc.M114.570838
Nguyen, Khanh Quynh N ; Tsou, Wen I. ; Calarese, Daniel A. ; Kimani, Stanley G. ; Singh, Sukhwinder ; Hsieh, Shelly ; Liu, Yongzhang ; Lu, Bin ; Wu, Yi ; Garforth, Scott J. ; Almo, Steven C. ; Kotenko, Sergei V. ; Birge, Raymond B. / Overexpression of MERTK receptor tyrosine kinase in epithelial cancer cells drives efferocytosis in a gain-of-function capacity. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 37. pp. 25737-25749.
@article{4bf7f48ba2644994ad5bd9018374a5f1,
title = "Overexpression of MERTK receptor tyrosine kinase in epithelial cancer cells drives efferocytosis in a gain-of-function capacity",
abstract = "MERTK, a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases, has complex and diverse roles in cell biology. On the one hand, knock-out of MERTK results in agedependent autoimmunity characterized by failure of apoptotic cell clearance, while on the other, MERTK overexpression in cancer drives classical oncogene pathways leading to cell transformation. To better understand the interplay between cell transformation and efferocytosis, we stably expressed MERTK in human MCF10A cells, a non-tumorigenic breast epithelial cell line devoid of endogenous MERTK. While stable expression of MERTK in MCF10A resulted in enhanced motility and AKTmediated chemoprotection, MERTK-10A cells did not form stable colonies in soft agar, or enhance proliferation compared with parental MCF10A cells. Concomitant to chemoresistance, MERTK also stimulated efferocytosis in a gain-of-function capacity. However, unlike AXL, MERTK activation was highly dependent on apoptotic cells, suggestingMERTKmay preferentially interface with phosphatidylserine. Consistent with this idea, knockdown ofMERTKin breast cancer cellsMDA-MB231 reduced efferocytosis, while transient or stable expression of MERTK stimulated apoptotic cell clearance in all cell lines tested. Moreover, human breast cancer cells with higher endogenous MERTK showed higher levels of efferocytosis that could be blocked by solubleTAMreceptors. Finally, through MERTK, apoptotic cells induced PD-L1 expression, an immune checkpoint blockade, suggesting that cancer cells may adopt MERTKdriven efferocytosis as an immune suppression mechanism for their advantage. These data collectively identify MERTK as a significant link between cancer progression and efferocytosis, and a potentially unrealized tumor-promoting event when MERTK is overexpressed in epithelial cells.",
author = "Nguyen, {Khanh Quynh N} and Tsou, {Wen I.} and Calarese, {Daniel A.} and Kimani, {Stanley G.} and Sukhwinder Singh and Shelly Hsieh and Yongzhang Liu and Bin Lu and Yi Wu and Garforth, {Scott J.} and Almo, {Steven C.} and Kotenko, {Sergei V.} and Birge, {Raymond B.}",
year = "2014",
month = "9",
day = "12",
doi = "10.1074/jbc.M114.570838",
language = "English (US)",
volume = "289",
pages = "25737--25749",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "37",

}

TY - JOUR

T1 - Overexpression of MERTK receptor tyrosine kinase in epithelial cancer cells drives efferocytosis in a gain-of-function capacity

AU - Nguyen, Khanh Quynh N

AU - Tsou, Wen I.

AU - Calarese, Daniel A.

AU - Kimani, Stanley G.

AU - Singh, Sukhwinder

AU - Hsieh, Shelly

AU - Liu, Yongzhang

AU - Lu, Bin

AU - Wu, Yi

AU - Garforth, Scott J.

AU - Almo, Steven C.

AU - Kotenko, Sergei V.

AU - Birge, Raymond B.

PY - 2014/9/12

Y1 - 2014/9/12

N2 - MERTK, a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases, has complex and diverse roles in cell biology. On the one hand, knock-out of MERTK results in agedependent autoimmunity characterized by failure of apoptotic cell clearance, while on the other, MERTK overexpression in cancer drives classical oncogene pathways leading to cell transformation. To better understand the interplay between cell transformation and efferocytosis, we stably expressed MERTK in human MCF10A cells, a non-tumorigenic breast epithelial cell line devoid of endogenous MERTK. While stable expression of MERTK in MCF10A resulted in enhanced motility and AKTmediated chemoprotection, MERTK-10A cells did not form stable colonies in soft agar, or enhance proliferation compared with parental MCF10A cells. Concomitant to chemoresistance, MERTK also stimulated efferocytosis in a gain-of-function capacity. However, unlike AXL, MERTK activation was highly dependent on apoptotic cells, suggestingMERTKmay preferentially interface with phosphatidylserine. Consistent with this idea, knockdown ofMERTKin breast cancer cellsMDA-MB231 reduced efferocytosis, while transient or stable expression of MERTK stimulated apoptotic cell clearance in all cell lines tested. Moreover, human breast cancer cells with higher endogenous MERTK showed higher levels of efferocytosis that could be blocked by solubleTAMreceptors. Finally, through MERTK, apoptotic cells induced PD-L1 expression, an immune checkpoint blockade, suggesting that cancer cells may adopt MERTKdriven efferocytosis as an immune suppression mechanism for their advantage. These data collectively identify MERTK as a significant link between cancer progression and efferocytosis, and a potentially unrealized tumor-promoting event when MERTK is overexpressed in epithelial cells.

AB - MERTK, a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases, has complex and diverse roles in cell biology. On the one hand, knock-out of MERTK results in agedependent autoimmunity characterized by failure of apoptotic cell clearance, while on the other, MERTK overexpression in cancer drives classical oncogene pathways leading to cell transformation. To better understand the interplay between cell transformation and efferocytosis, we stably expressed MERTK in human MCF10A cells, a non-tumorigenic breast epithelial cell line devoid of endogenous MERTK. While stable expression of MERTK in MCF10A resulted in enhanced motility and AKTmediated chemoprotection, MERTK-10A cells did not form stable colonies in soft agar, or enhance proliferation compared with parental MCF10A cells. Concomitant to chemoresistance, MERTK also stimulated efferocytosis in a gain-of-function capacity. However, unlike AXL, MERTK activation was highly dependent on apoptotic cells, suggestingMERTKmay preferentially interface with phosphatidylserine. Consistent with this idea, knockdown ofMERTKin breast cancer cellsMDA-MB231 reduced efferocytosis, while transient or stable expression of MERTK stimulated apoptotic cell clearance in all cell lines tested. Moreover, human breast cancer cells with higher endogenous MERTK showed higher levels of efferocytosis that could be blocked by solubleTAMreceptors. Finally, through MERTK, apoptotic cells induced PD-L1 expression, an immune checkpoint blockade, suggesting that cancer cells may adopt MERTKdriven efferocytosis as an immune suppression mechanism for their advantage. These data collectively identify MERTK as a significant link between cancer progression and efferocytosis, and a potentially unrealized tumor-promoting event when MERTK is overexpressed in epithelial cells.

UR - http://www.scopus.com/inward/record.url?scp=84907164518&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907164518&partnerID=8YFLogxK

U2 - 10.1074/jbc.M114.570838

DO - 10.1074/jbc.M114.570838

M3 - Article

C2 - 25074939

AN - SCOPUS:84907164518

VL - 289

SP - 25737

EP - 25749

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 37

ER -