cancers Review The Emerging Role of TYRO3 as a Therapeutic Target in Cancer Sherri K. Smart 1,2, Eleana Vasileiadi 1,2, Xiaodong Wang 3, Deborah DeRyckere 1,2 and Douglas K. Graham 1,2,* 1 Department of Pediatrics, Emory University, Atlanta, GA 30322, USA; [email protected] (S.K.S.); [email protected] (E.V.); [email protected] (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; [email protected] * Correspondence: [email protected]; Tel.: +404-785-3874; Fax: +404-785-1178 Received: 1 November 2018; Accepted: 24 November 2018; Published: 29 November 2018 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. Keywords: TYRO3; MERTK; AXL; TAM family; receptor tyrosine kinase; targeted therapy; signaling pathway; cancer 1. Introduction TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) family of transmembrane receptor tyrosine kinases [1], which share overlapping functions in tumorigenesis and suppression of anti-tumor immunity [2]. While roles for MERTK and AXL in these processes have been well-described, less is known about the roles for TYRO3. In addition, many studies have assessed the effects of TYRO3 inhibition in conjunction with inhibition of MERTK and/or AXL in an effort to evaluate overlapping functions and have not evaluated contributions of the individual family members. Similarly, studies describing the effects of TAM kinase ligands in biologic systems do not always evaluate the contributions of individual family members. Here we provide a brief review of what is known about specific roles for TYRO3 in normal physiology and a more comprehensive review of the current literature demonstrating roles for TYRO3 in tumorigenesis. 2. Structure, Expression, and Mutations 2.1. TYRO3 Structure TAM kinases have a distinct structure composed of an extracellular domain, a single helix transmembrane domain, and an intracellular domain (Figure1A) [ 3–6]. The extracellular domain Cancers 2018, 10, 474; doi:10.3390/cancers10120474 www.mdpi.com/journal/cancers Cancers 2018, 10, 474 2 of 27 containsCancers two 2018,fibronectin 10, x type III and two Ig domains and the cytoplasmic domain mediates2 of 26 kinase activitycontains and actstwo fibronectin as a binding type site III for and other two Ig molecules. domains and The the family cytoplasmic is further domain distinguished mediates kinase from other tyrosineactivity kinases and acts by as the a binding presence site of for a other conserved molecules. KW(I/L)A(I/L)ES The family is further sequence distinguished in the kinasefrom other domain. Aminotyrosine acids kinases 3 and 5by within the presence this sequence of a conserved are leucine KW(I/L)A(I/L)ES (L) in TYRO3 sequence and isoleucine in the kinase (I) in domain MERTK. and AXL.Amino TYRO3 acids was 3 independentlyand 5 within this cloned sequence by are numerous leucine (L) groups in TYRO3 and and as a isoleucine result, has (I) been in MERTK called and by many names,AXL. including TYRO3 wasTYRO3 independently, SKY, RSE cloned, BYK byand numerousTIF in humans, groups andDtk as, Rse a result,, Brt, Etk2has beenand calledTyro3 byin mice, and REKmanyin names, chickens including [3,7]. TYRO3 The human, SKY, TYRO3RSE, BYK protein and TIF contains in humans, 890 Dtk amino, Rse, acidsBrt, Etk2 and and has Tyro3 a predicted in molecularmice, and weight REK of in 97 chickens kDa, although [3,7]. The the human actual TYRO3 molecular protein weight contains ranges 890 between amino acids 120–140 and kDahas a due to post-translationalpredicted molecular modifications, weight of 97 including kDa, although glycosylation the actual molecular [8–11]. Two weight splice range variantss between of TYRO3120–140 have kDa due to post-translational modifications, including glycosylation [8–11]. Two splice variants of been demonstrated and a third predicted containing either exon 2A, 2B, or 2C, which encode the TYRO3 have been demonstrated and a third predicted containing either exon 2A, 2B, or 2C, which signalencode sequence the signal in the sequence extracellular in the domainextracellular and maydomain be and important may be forimportant post-translational for post-translational modifications, localizationmodifications, and function localization [6, 8and,12 ].function Next generation[6,8,12]. Next computational generation computational modeling modeling methods methods that rely on publicly-availablethat rely on publicly cDNA-available and mRNA cDNA and data mRNA predicted data predict the existenceed the existence of up to of 9up TYRO3 to 9 TYRO3 splice splice variants containingvariants overlapping containing overlapping exons, alternative exons, alternative splicing splicing or intron or retention,intron retention although, although these these have have not been verifiednot been in cell-based verified in assays cell-based [13]. assays [13]. A TYRO3 B PROS1 GAS6 C Figure Figure 1. TYRO3 1. TYRO3 Structure Structure and and Activation. Activation. ( A)) TYRO3 TYRO3 is is a a890 890 amino amino acid acid transmembrane transmembrane protein protein composedcomposed of two of two extracellular extracellular IgG IgG like like domainsdomains (amino (amino acids acids 60 60–117–117 and and 156 156–203),–203), two twoextracellular extracellular Figure 1: TYRO3 Structure and Activation. A) TYRO3 is a 890 amino acid transmembrane protein fibronectin III domains (amino acids 224–313 and 322–409), a transmembrane portion (amino acids fibronectincomposed III of domains two extracellular (amino IgG acids like 224–313domains (amino and 322–409), acids 60-117 a transmembrane and 156-203), two portion extracellular (amino acids 430–450) and an intracellular kinase domain (amino acids 525–776). The conserved KW(I/L)A(I/L)ES 430–450)fibronectin and anIII domains intracellular (amino kinase acids 224 domain-313 and (amino 322-409), acids a transmembrane 525–776). The conservedportion (amino KW(I/L)A(I/L)ES acids 430- sequence in the kinase domain is unique to the TAM-family receptor tyrosine kinases. (B) The best sequence450) and in an the intracellular kinase domain kinase domain is unique (amino to the acids TAM-family 525-776). The receptor conserved tyrosine KW(I/L)A(I/L)ES kinases. sequence (B) The best characterized TYRO3 ligands are Protein S (PROS1) and GAS6, which share ~43% sequence homology characterizedin the kinase TYRO3 domain ligands is unique are to Proteinthe TAM S-family (PROS1) receptor and tyrosine GAS6, whichkinases. share B) The ~43% best characterized sequence homology TYRO3and contain ligands a are Gla Protein domain, S (PROS1) 4 EGF-like and domains,GAS6, which and share two Laminin~43% sequence G-like homologydomains. (andC) Activationcontain a Gla of anddomain,TYRO3. contain 4 PROS1 aEGF Gla-like domain,or domains, GAS6 binds 4 EGF-likeand totwo phosphatidylserine Laminin domains, G-like and domains. twoon membranes Laminin C) Activation G-likeof apoptotic of TYRO3. domains. and PROS1 virus (C or)- ActivationGAS6infected of TYRO3.bindscells PROS1andto phosphatidylserine promotes or GAS6 dimerization, binds on membranes to phosphatidylserineautophosphorylation of apoptotic andand on membranesvirusactivation-infected of TYRO3. ofcells apoptotic and Ligand promotes and independent virus-infected cellsdimerization,activation and promotes of autophosphoTYRO3 dimerization, has alsorylation been autophosphorylation and reported. activation of TYRO3. and Ligand activation independent of TYRO3. activation Ligand of TYRO3 independent has activationalso been of reported. TYRO3 has also been reported. 2.2. Physiologic TYRO3 Expression 2.2. Physiologic TYRO3 Expression TYRO3 is physiologically expressed in a variety of tissues and is most prominent in the nervous system.TYRO3 In is the physiologically brain, TYRO3 is expressed found in endothelial in a variety cells of [14] tissues, neurons and is[15 most–17], oligodendrocytes prominent in the [18] nervous, system.and Inthe the hippocampus brain, TYRO3 [19] isand found TYRO3 in endothelialis also expressed cells in [14 Schwann], neurons cells [15 in– the17], peripheral oligodendrocytes nervous [18], and thesystem hippocampus [20]. In the hematopoietic [19] and TYRO3 system, is alsoTYRO3 expressed is express ined Schwann in dendritic cells cells in [21,22] the peripheral, natural killer nervous systemcells [ 20[23]]., monocytes