The Emerging Role of TYRO3 as a Therapeutic Target in Cancer

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Abstract

The TAM family (TYRO3, AXL, MERTK) tyrosine kinases play roles in diverse biological processes including immune regulation, clearance of apoptotic cells, platelet aggregation, and cell proliferation, survival, and migration. While AXL and MERTK have been extensively studied, less is known about TYRO3. Recent studies revealed roles for TYRO3 in cancer and suggest TYRO3 as a therapeutic target in this context. TYRO3 is overexpressed in many types of cancer and functions to promote tumor cell survival and/or proliferation, metastasis, and resistance to chemotherapy. In addition, higher levels of TYRO3 expression have been associated with decreased overall survival in patients with colorectal, hepatocellular, and breast cancers. Here we review the physiological roles for TYRO3 and its expression and functions in cancer cells and the tumor microenvironment, with emphasis on the signaling pathways that are regulated downstream of TYRO3 and emerging roles for TYRO3 in the immune system. Translational agents that target TYRO3 are also described.

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Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

Klarisa Rikova, Ailan Guo, Qingfu Zeng … (2008)

Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.

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Autoimmunity and the clearance of dead cells.

Shigekazu NAGATA, Rikinari Hanayama, Kohki Kawane (2010)

To maintain organismal homeostasis, phagocytes engulf dead cells, which are recognized as dead by virtue of a characteristic "eat me" signal exposed on their surface. The dead cells are then transferred to lysosomes, where their cellular components are degraded for reuse. Inefficient engulfment of dead cells activates the immune system, causing disease such as systemic lupus erythematosus, and if the DNA of the dead cells is not properly degraded, the innate immune response becomes activated, leading to severe anemia and chronic arthritis. Here, we discuss how the endogenous components of dead cells activate the immune system through both extracellular and intracellular pathways. (c) 2010 Elsevier Inc. All rights reserved.

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Minireview: Cyclin D1: normal and abnormal functions.

Maofu Fu, Chenguang Wang, Zhiping Li … (2004)

Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein and promotes progression through the G1-S phase of the cell cycle. Amplification or overexpression of cyclin D1 plays pivotal roles in the development of a subset of human cancers including parathyroid adenoma, breast cancer, colon cancer, lymphoma, melanoma, and prostate cancer. Of the three D-type cyclins, each of which binds cyclin-dependent kinase (CDK), it is cyclin D1 overexpression that is predominantly associated with human tumorigenesis and cellular metastases. In recent years accumulating evidence suggests that in addition to its original description as a CDK-dependent regulator of the cell cycle, cyclin D1 also conveys cell cycle or CDK-independent functions. Cyclin D1 associates with, and regulates activity of, transcription factors, coactivators and corepressors that govern histone acetylation and chromatin remodeling proteins. The recent findings that cyclin D1 regulates cellular metabolism, fat cell differentiation and cellular migration have refocused attention on novel functions of cyclin D1 and their possible role in tumorigenesis. In this review, both the classic and novel functions of cyclin D1 are discussed with emphasis on the CDK-independent functions of cyclin D1.

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Author and article information

Journal

Journal ID (nlm-ta): Cancers (Basel)

Journal ID (iso-abbrev): Cancers (Basel)

Journal ID (publisher-id): cancers

Title: Cancers

Publisher: MDPI

ISSN (Electronic): 2072-6694

Publication date (Electronic): 29 November 2018

Publication date Collection: December 2018

Volume: 10

Issue: 12

Electronic Location Identifier: 474

Affiliations

[1 ]Department of Pediatrics, Emory University, Atlanta, GA 30322, USA; sherri.smart@ 123456choa.org (S.K.S.); eleana.vasileiadi@ 123456emory.edu (E.V.); deborah.deryckere@ 123456emory.edu (D.D.)

[2 ]Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA

[3 ]Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; xiaodonw@ 123456email.unc.edu

Author notes

[* ]Correspondence: douglas.graham@ 123456choa.org ; Tel.: +404-785-3874; Fax: +404-785-1178

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Deborah DeRyckere https://orcid.org/0000-0002-7457-9006

Article

Publisher ID: cancers-10-00474

DOI: 10.3390/cancers10120474

PMC ID: 6316664

PubMed ID: 30501104

SO-VID: f2e960a3-c91d-4e22-b08e-7d3e372ca14c

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

History

Date received : 01 November 2018

Date accepted : 24 November 2018

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The Emerging Role of TYRO3 as a Therapeutic Target in Cancer

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Abstract

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Cancer Metabolism

Most cited references 125

Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

Autoimmunity and the clearance of dead cells.

Minireview: Cyclin D1: normal and abnormal functions.

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Cited by 37

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