TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer
Introduction
Receptor tyrosine kinases (RTKs) are transmembrane proteins which transduce signals from the extracellular environment to the cytoplasm and nucleus. In this manner, RTKs regulate normal cellular processes, including survival, growth, differentiation, adhesion, and motility. Abnormal expression or activity of RTKs can render them transforming in cellular and animal models. Furthermore, increased RTK expression or activation has been directly implicated in the pathogenesis of myriad human cancers leading to intense interest in the development and testing of tyrosine kinase inhibitors as cancer therapeutics.
The 58 RTKs in the human genome are classified into 20 families by amino acid sequence identity within the kinase domain and structural similarities within their extracellular regions (Robinson et al., 2000). The focus of this review is the TAM family which includes Tyro‐3, Axl, and Mer, three receptors which share the vitamin K‐dependent ligands Gas6 and Protein S. Signaling pathways employed by the TAM family have been recently elucidated and shown to mediate diverse cellular functions, including macrophage clearance of apoptotic cells, platelet aggregation, and natural killer (NK) cell differentiation. This review will highlight the role of these RTKs in normal cellular function as well as the mechanisms employed by the TAM family to promote oncogenesis. In addition, we will discuss possible means of targeted inhibition of the TAM family in the treatment of human cancer.
Section snippets
Molecular Biology of TAM Receptors
Like all RTKs, Tyro‐3, Axl, and Mer contain an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain. The TAM family is distinguished from other RTKs by a conserved sequence, KW(I/L)A(I/L)ES, within the kinase domain and adhesion molecule‐like domains in the extracellular region (Fig. 1A). More specifically, two immunoglobulin‐like (Ig) domains and two fibronectin type III (FNIII) domains comprise nearly the entire ectodomain of each family member. These
Involvement of TAM Receptors in Cancer
There are many ways that protooncogenes such as TAM receptors can be activated, including gene amplification and mutations, proteolytic cleavage, and altered protein expression. These modifications have all been described for TAM receptors and each may result in generation of a constitutively active enzyme and/or over‐ or ectopically expressed proteins that are not subject to normal cellular regulation. Most of the TAM receptor gene mutations reported involve Mer and retinal degeneration (
Potential Therapeutic Applications
Several studies have validated the therapeutic potential of targeting the TAM family in cancer therapy (Table III). Axl RTK and the ligand Gas6 are overexpressed in human glioma cell lines and malignant glioma patient samples when evaluated by microarray, Northern blot, Western blot, and immunohistochemistry analysis (Vajkoczy et al., 2006), leading to baseline constitutive activation of Axl RTK. In order to further investigate the role of Axl in glioblastoma tumorigenesis, these researchers
Conclusions
In the last decade, research has established the link between abnormal TAM receptor expression and oncogenesis. All three receptors are over‐ or ectopically expressed in a wide spectrum of human cancers, and overexpression of TAM receptors is sufficient to transform cells. TAM receptor inhibitions in animal xenograft tumor models of glioblastoma and breast cancer have provided preliminary validation of this receptor family as a cancer therapy target.
More than half of the known RTKs have been
Acknowledgements
Research in the authors' laboratories is supported by grants from the G&P Foundation for Cancer Research (#030, DKG), the Brent Eley Foundation (AKK) and the NCI (HSE). Douglas K. Graham is the Damon Runyon-Novartis Clinical Investigator supported in part by the Damon Runyon Cancer Research Foundation (CI‐39–07). The authors thank Drs. James DeGregori, Deborah DeRyckere, and Peter Henson for critical review of the manuscript.
References (175)
- et al.
Estrogen dependent expression of the receptor tyrosine kinase axl in normal and malignant human breast
Ann. Oncol.
(2001) - et al.
Rek, a gene expressed in retina and brain, encodes a receptor tyrosine kinase of the Axl/Tyro3 family
J. Biol. Chem.
(1996) - et al.
Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays
Blood
(2001) - et al.
Gas6 anti‐apoptotic signaling requires NF‐kappa B activation
J. Biol. Chem.
(2001) - et al.
GAS6 induces Axl‐mediated chemotaxis of vascular smooth muscle cells
J. Biol. Chem.
(1998) - et al.
Reevaluation of the roles of protein S and Gas6 as ligands for the receptor tyrosine kinase Rse/Tyro 3
Cell
(1995) - et al.
Cell type‐specific expression of the IkappaB kinases determines the significance of phosphatidylinositol 3‐kinase/Akt signaling to NF‐kappa B activation
J. Biol. Chem.
(2004) - et al.
Mer receptor tyrosine kinase signaling: Prevention of apoptosis and alteration of cytoskeletal architecture without stimulation or proliferation
J. Biol. Chem.
(2002) - et al.
A Web‐based data warehouse on gene expression in human malignant melanoma
J. Invest. Dermatol.
(2007) - et al.
Interaction of Axl receptor tyrosine kinase with C1‐TEN, a novel C1 domain‐containing protein with homology to tensin
Biochem. Biophys. Res. Commun.
(2002)
The Ran binding protein RanBPM interacts with Axl and Sky receptor tyrosine kinases
Int. J. Biochem. Cell Biol.
Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases
Cytokine Growth Factor Rev.
The hallmarks of cancer
Cell
A phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14.18 in patients with neuroblastoma
Eur. J. Cancer
Ligand recognition and homophilic interactions in Tyro3: Structural insights into the Axl/Tyro3 receptor tyrosine kinase family
J. Biol. Chem.
The proto‐oncogene of v‐eyk (v‐ryk) is a novel receptor‐type protein tyrosine kinase with extracellular Ig/GN‐III domains
J. Biol. Chem.
Mechanism of stimulation of osteoclastic bone resorption through Gas6/Tyro 3, a receptor tyrosine kinase signaling, in mouse osteoclasts
J. Biol. Chem.
SOCS1/JAB is a negative regulator of LPS‐induced macrophage activation
Immunity
An extended family of protein‐tyrosine kinase genes differentially expressed in the vertebrate nervous system
Neuron
Transforming activity of receptor tyrosine kinase tyro3 is mediated, at least in part, by the PI3 kinase‐signaling pathway
Blood
Macrophage regulation by Tyro 3 family receptors
Curr. Opin. Immunol.
Analysis of the murine Dtk gene identifies conservation of genomic structure within a new receptor tyrosine kinase subfamily
Genomics
Cholesterol‐induced apoptotic macrophages elicit an inflammatory response in phagocytes, which is partially attenuated by the Mer receptor
J. Biol. Chem.
Identification of the major autophosphorylation sites of Nyk/Mer, an NCAM‐related receptor tyrosine kinase
J. Biol. Chem.
An SH2 domain‐dependent, phosphotyrosine‐independent interaction between Vav1 and the Mer receptor tyrosine kinase: A mechanism for localizing guanine nucleotide‐exchange factor action
J. Biol. Chem.
rse, a novel receptor‐type tyrosine kinase with homology to Axl/Ufo, is expressed at high levels in the brain
J. Biol. Chem.
Growth arrest‐specific gene 6 (Gas6)/adhesion related kinase (Ark) signaling promotes gonadotropin‐releasing hormone neuronal survival via extracellular signal‐regulated kinase (ERK) and Akt
Mol. Endocrinol.
Novel mechanism for gonadotropin‐releasing hormone neuronal migration involving Gas6/Ark signaling to p38 mitogen‐activated protein kinase
Mol. Cell Biol.
Serum‐derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells
Nat. Immunol.
Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis
Nat. Med.
Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy
J. Clin. Invest.
The mer receptor tyrosine kinase: Expression and function suggest a role in innate immunity
Eur. J. Immunol.
The receptor tyrosine kinase ARK mediates cell aggregation by homophilic binding
Mol. Cell Biol.
Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation
Oncogene
Identification of four murine cDNAs encoding putative protein kinases from primitive embryonic stem cells differentiated in vitro
Proc. Natl. Acad. Sci. USA
Identification of alternative exons, including a novel exon, in the tyrosine kinase receptor gene Etk2/tyro3 that explain differences in 5′ cDNA sequences
Oncogene
Met, metastasis, motility and more
Nat. Rev. Mol. Cell Biol.
Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi‐substrate docking‐site
Oncogene
Soluble Axl is generated by ADAM10‐dependent cleavage and associates with Gas6 in mouse serum
Mol. Cell Biol.
A promiscuous liaison between IL‐15 receptor and Axl receptor tyrosine kinase in cell death control
EMBO J.
Determinants for transformation induced by the Axl receptor tyrosine kinase
Oncogene
A novel receptor tyrosine kinase, Mer, inhibits TNF‐alpha production and lipopolysaccharide‐induced endotoxic shock
J. Immunol.
Natural killer cell differentiation driven by Tyro3 receptor tyrosine kinases
Nat. Immunol.
Differential expression of the ufo/axl oncogene in human leukemia‐lymphoma cell lines
Leukemia
Identification and regulation of receptor tyrosine kinases Rse and Mer and their ligand Gas6 in testicular somatic cells
J. Androl.
Identification of Gas6 as a ligand for Mer, a neural cell adhesion molecule related receptor tyrosine kinase implicated in cellular transformation
Oncogene
Expression of the proto‐oncogene Axl in renal cell carcinoma
DNA Cell Biol.
Delayed apoptotic cell clearance and lupus‐like autoimmunity in mice lacking the c‐mer membrane tyrosine kinase
J. Exp. Med.
Cleavage and release of a soluble form of the receptor tyrosine kinase ARK in vitro and in vivo
J. Cell. Physiol.
Receptor tyrosine kinases expressed in metastatic colon cancer
Int. J. Cancer
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