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Stem Cells, Vol. 14, No. 1, 117-123, January 1996
© 1996 AlphaMed Press

CONCISE REVIEW

Role of c-Fes in Normal and Neoplastic Hematopoiesis

Karen E. Yatesa, Judith C. Gassona,b

a Division of Hematology-Oncology, Department of Medicine, UCLA School of Medicine, Los Angeles, California, USA;
b Department of Biological Chemistry, UCLA School of Medicine, Los Angeles, California, USA

Key Words. c-Fes • Tyrosine kinase • Hematopoiesis • c-Fps • Signal transduction • Leukemia

Dr. Judith C. Gasson, Division of Hematology-Oncology, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90095-1678, USA.


   Abstract
Top
 Abstract
Introduction
 Pattern of Expression
 Fes Function in Myeloid...
 Conclusion
 References
 
The study of oncogenes has provided numerous insights, not only into the mechanisms by which growth regulation becomes uncontrolled in cancer cells, but also into signal transduction processes which regulate the orderly proliferation and maturation of cells. c-fes/fps is a cellular oncogene which has been transduced frequently by mammalian and avian retroviruses. There are several features about Fes which suggest it may play a unique role in myeloid cell growth and differentiation. While it contains a tyrosine kinase and SH2 domain, there is no SH3 domain or carboxy terminal regulatory phosphotyrosine such as found in the Src family of kinases. Fes has a unique N-terminal domain of over 400 amino acids of unknown function. It has been implicated in signaling by a variety of hematopoietic growth factors, and is predominantly a nuclear protein.


   Introduction
Top
 Abstract
 Introduction
Pattern of Expression
 Fes Function in Myeloid...
 Conclusion
 References
 
c-fes is the cellular homolog of the transforming oncogene found in numerous mammalian and avian retroviruses, including the Snyder-Theilen feline sarcoma virus and the Fujinami sarcoma virus [1–3]. The oncogene product of the Snyder-Theilen feline sarcoma virus is an 85 kilodalton (kDa) fusion protein between the feline leukemia virus gag gene and c-fes [4], and the product of the avian Fujinami sarcoma virus is a 130 kDa Gag/Fps fusion protein [5]. Generally, "Fes" is used in reference to the 93 kDa mammalian proteins (human, murine or feline), and "Fps" refers to the 98 kDa avian form, also known as normal cell protein98 or NCP98 (Fig. 1Go). The human Fes protein is 94% similar to feline Fes at the amino acid level, 90% similar to murine Fes, and 70% similar to avian Fps [6,7]. A Fes-related protein has been described in Drosophila melanogaster, called dfps85D, that is 60% similar to human Fes [8].



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  		Fig. 1. Structural features of Fes family proteins. Schematic drawing of the various Fes proteins with the unique N-terminal region, SH2, and kinase domains indicated. Complete DNA and protein sequences are in the following references: human c-Fes [6], Fer [10], FerT [11], Fps [66] and p130 Gag-Fps [5].

 
c-Fes, its avian counterpart Fps, and a closely related kinase, Fer, are members of a family of non-receptor kinases characterized by a unique 400-amino acid N-terminal region of unknown function, the presence of tyrosine kinase and SH2 domains, but absence of an SH3 domain and a carboxy terminal regulatory tyrosine [9,10] (Fig. 1Go). Fer was identified by screening a human fibroblast cDNA library with a v-abl probe at low stringency [10], and the 94 kDa protein was found to have a 49% overall amino acid homology with the 93 kDa Fes protein. Fer protein has been observed in a variety of cell lines and tissues [10]. A testis-specific transcript of Fer, called ferT, encodes a truncated (51 kDa) Fer protein [11] that is expressed in spermatocytes during a specific stage of meiosis [12].


   Pattern of Expression
Top
 Abstract
 Introduction
 Pattern of Expression
Fes Function in Myeloid...
 Conclusion
 References
 
In contrast to Fer, expression of Fes appears to be limited in adult tissues. Greer et al. [13] demonstrated expression of Fes in vascular endothelial cells of human and mouse tissues. A number of studies on the expression pattern of Fes/Fps proteins indicates close correlation with hematopoietic progenitor cells and mature cells of the myeloid lineage. Expression of c-Fps has been detected in macrophages and granulocytic cells [14], and human c-Fes is found in the promyelocytic cell line, HL-60, the KG-1 myeloblast cell line, primary acute myelogenous leukemia (AML) cells and, less commonly, in human erythroleukemia cell lines [15]. c-fes mRNA was analyzed in various normal hematopoietic cell populations and found to be expressed exclusively in myeloid cells [16]. Levels of c-fes mRNA have also been correlated with GM-CSF-responsiveness in differentiating myeloid cells [17]. Recently, an extensive analysis of c-fes expression in human and murine ontogenic development revealed high levels of mRNA in the developing central nervous system and cartilage [18]. The same study confirmed that expression in adult tissue was limited to hematopoietic cells, and showed that mRNA levels in highly purified (CD34+) progenitor cells remained constant during myelomonocytic differentiation but decreased during erythroid differentiation [18].

A survey of various human tumors revealed high levels of c-fes mRNA expression in most fresh AML and CML samples analyzed. Expression of c-fes mRNA was also observed in lung malignancies, certain lymphomas and lymphocytic leukemias, and in two of nine renal malignancies [19]. More recently, Smithgall et al. [20] confirmed elevated expression of c-fes mRNA in adult myeloid leukemias in the absence of gene amplification, and also reported low levels of expression in certain lymphoid malignancies.

Role of c-Fes in Cellular Transformation
The frequency with which c-fes has been transduced, together with its expression in a number of malignancies, indicated that perhaps the Fes protein, when overexpressed, would cause transformation of a cell. Indeed, transgenic mice expressing v-fps develop a wide variety of tumors, including lymphomas, thymomas, fibrosarcomas, angiosarcomas, hemangiomas and neurofibrosarcomas [21]. Infection of chicken bone marrow cells with retroviruses containing the v-fps oncogene allows growth of colonies in semisolid medium in the absence of exogenously added growth factors [22], and Rat-2 fibroblasts are readily transformed by v-fps.

A number of studies on the structure-function of v-Fes/Fps proteins gave insight as to which regions of the molecule are essential for transformation of target cells [23–25]. In particular, a key observation that came from this body of work was that a conserved lysine in the ATP binding site is essential for kinase activity [26]. This finding ultimately led other investigators to elucidate the function of different tyrosine kinases by a dominant-negative approach [27, 28]. However, further extrapolation of the data on viral Fes/Fps proteins to the functional characteristics of their cellular counterparts is limited. First, c-Fes and v-Fes are not identical; in addition to the Gag fusion, there are amino acid differences throughout the proteins, particularly in the amino-terminal regions [6]. Second, the normal cellular Fes protein does not itself appear to be able to transform cells; the human c-fes gene product can be overexpressed up to 50-fold in Rat-2 fibroblasts without causing transformation [29]. In addition, myeloid overexpression of the human c-fes gene under control of its endogenous promoter in transgenic mice did not generate tumors and had no apparent effects on hematopoiesis [30]. Numerous studies on the transformation potential of Fes have used viral expression vectors and showed that c-fes and c-fps, without addition of gag sequences, do not transform fibroblasts [29, 31, 32]. In contrast, one group of investigators reported that overexpression of Fes by a particular viral construct leads to transformation of fibroblasts [33].

Thus, it appears that overexpression of c-Fes is insufficient to cause transformation of cells. Alternative roles for Fes in cellular transformation have been suggested. For example, a study of fresh AML samples demonstrated a correlation between autocrine expression of GM-CSF, factor-independent growth and high levels of c-fes mRNA [34]. An earlier study showed that GM-CSF-responsive AML blasts contained high levels of c-fes mRNA, whereas nonresponsive cells did not [17].

Other studies have sought to reveal the role of Fes in neoplasia by looking at its interactions with cellular machinery known to be involved in transformation. In work by Greer et al. [13], the tight association of v-Fes with the plasma membrane was mimicked by changing the amino-terminus of Fes to encode the first six amino acids of Src. These amino acids include a signal for myristoylation, which is known to promote membrane association [35]. The myristoylated Fes protein was tightly associated with membranes, and had increased kinase activity in vitro. Transgenic mice expressing the myristoylated Fes were hypervascular and progressed to multifocal hemangiomas [13].

A possible connection of Fes to Bcr/Ablmediated leukemogenesis has also been suggested. Bcr/Abl is an oncogenic fusion protein which results from a chromosomal translocation that occurs in many CMLs and AMLs [36]. Ernst, Slattery, and Griffin [37] noted that tyrosine phosphorylation of Fes was increased in CML cells that expressed Bcr/Abl, although they were unable to demonstrate a direct interaction of the proteins by immunoprecipitation. However, Maru et al. [38] used a baculovirus expression system and immunoprecipitation to show that Fes associates with the Bcr protein in transfected Sf-9 insect cells via its amino-terminal and SH2 domains. In addition, they saw that v-Fps could phosphorylate Bcr in vivo in fibroblasts, but a deletion mutant of v-Fps lacking the Bcr-binding amino-terminal region did not.

Fes may be involved in the Ras signaling pathway. The importance of the Ras family of nucleotide exchange factors in normal and neoplastic cell signaling has been well-established. The GTPase-activating protein, Ras-GAP, can be phosphorylated by Fes in an in vitro kinase assay [39]. The association of Fes with Ras-GAP is mediated by the Ras-GAP SH2 domains, and requires a functional kinase domain in Fes. However, the effect of phosphorylation by Fes on Ras-GAP has not been determined. v-Fps has been shown to associate with the nucleotide exchange factor, Sos. Bcr immunoprecipitated from fibroblasts expressing v-Fps was found to be in a complex with Sos and GRB2, an adaptor protein [38]. GRB2 is known to link signaling through tyrosine kinases to the Ras pathway [40, 41]. In addition, Bcr/Abl interacts with GRB2, and this interaction is a key step in Bcr/Abl-mediated transformation [42]. Despite these intriguing observations, the precise role of c-Fes in cellular transformation remains to be defined.


   Fes Function in Myeloid Cells
Top
 Abstract
 Introduction
 Pattern of Expression
 Fes Function in Myeloid...
Conclusion
 References
 
What, then, is the physiological role of c-Fes in the cells in which it is normally expressed, those of the myeloid lineage? Several lines of evidence indicate that Fes may be involved in myeloid cell growth and/or differentiation. First, Fes protein has been shown to be expressed in CD34+ hematopoietic progenitor cells [18; and Yates and Gasson, unpublished results] but not in mature lymphoid cells [16]. Second, antisense oligonucleotides directed against c-fes have been reported to block chemically-induced granulocytic differentiation of HL-60 cells [43, 44]. The most complete studies on the role of Fes in differentiation of myeloid cells have been conducted by Glazer's group, using two leukemic cell lines, HL-60 and K562. In studies on HL-60 cells, they demonstrated coordinate upregulation of c-fes mRNA and GM-CSF receptors during granulocytic differentiation [45, 46]. Additionally, they have shown that introduction of the c-fes gene into K562 cells induces differentiation along the granulocytic phenotype [46], and mutation of the major autophosphorylation site at tyrosine713 attenuates this differentiation process [47].

The apparent association between the function of Fes and GM-CSF action in myeloid differentiation has led a number of investigators to search for a biochemical connection between the myeloid growth factor receptors and c-Fes. These growth factor receptors are multisubunit complexes and are members of a cytokine receptor superfamily [48]. While one of the earliest biochemical events to be detected following activation of these receptors is phosphorylation of proteins on tyrosine residues [49], none of the receptors in the cytokine receptor superfamily contains intrinsic tyrosine kinase activity. Thus, one or more tyrosine kinases may fulfill this function.

The GM-CSF, interleukin 3 (IL-3) and IL-5 receptors consist of a ligand-binding alpha subunit and a common beta subunit. The beta subunit alone does not bind any of these factors, but creates a high-affinity binding site when complexed with the alpha chain [50]. In contrast, the erythropoietin (Epo) receptor is thought to function as a homodimer [51]. Using mutational analysis of the common beta subunit, Miyajima's group demonstrated that more than one region of this subunit may interact with tyrosine kinases. Furthermore, tyrosine kinases may function sequentially in signal transduction [52, 53]. In addition, mutational analysis of the GM-CSF receptor alpha subunit demonstrates that the cytoplasmic domain of this receptor subunit is also required for transduction of a proliferative signal [54, 55]. These data support the hypothesis that ligand binding induces hetero- and/or homodimerization of receptor subunits to bring different nonreceptor tyrosine kinases into proximity, leading to auto- and cross-phosphorylation. Indeed, an elegant series of studies was recently published which showed compelling evidence for a role of the JAK2 protein tyrosine kinase in signal transduction by a number of cytokines, including IL-3, Epo, growth hormone and GM-CSF [56–59].

Hanazono et al. [60] reported increased tyrosine phosphorylation and kinase activity of c-Fes in TF-1 cells treated with GM-CSF or IL-3. They used coimmunoprecipitation to show physical association between c-Fes and the beta chain of the human GM-CSF receptor. These investigators also reported increased tyrosine phosphorylation and kinase activity of c-Fes in response to treatment of TF-1 cells with Epo [61]. However, other groups have not been able to duplicate their results [57, 59]; thus, some controversy exists regarding the role of Fes in cytokine-mediated signaling.

Our studies on the subcellular localization of Fes raise intriguing possibilities for its function in myeloid cells [62]. We have shown, by both biochemical fractionation and immunocytochemistry, that the majority of Fes is found within the nucleus. A few tyrosine kinases have been localized to the nucleus [63], including Abl and the other members of the Fes family, Fer [64] and FerT [65]. The function of Fer in the nucleus is not known. The Abl tyrosine kinase has been shown to have a growth inhibitory function, which is lost when the protein is translocated to the cytosol by the fusion of bcr sequences [28].

To begin to study the function of Fes in the nucleus, we developed a transient expression system in COS-1 cells. Taking cellular equivalents of the fractions into account, biochemical fractionation of these cells shows that the majority of Fes protein is again present in the nucleus (Fig. 2Go). Immunoblot analysis of these cellular factors with antibody to a membrane protein, the glucose transporter, showed that the nuclear fraction was not significantly contaminated with the membrane fraction (data not shown). One difference between the distribution of Fes expressed in COS-1 cells versus myeloid cells is that we observe some Fes protein present in the cytosol. Previous studies with myeloid cells showed that Fes was not a cytoplasmic protein [62]. The protein present in the S45 cytosol may be a result of the high level of expression of Fes in COS-1 cells; some Fes may have leaked out of the nucleus or may be associated with the microsomal fraction, which is not pelleted at 45,000 g. Using this transient expression system, we can begin to define a role for nuclear c-Fes.



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  		Fig. 2. Biochemical fractionation of COS-1 cells transiently transfected with the human c-Fes expression plasmid, pONfes1. Anti-Fes immunoblot (antiserum #61) of cellular fraction prepared from COS-1 cells transiently expressing Fes. Fifteen µg of protein were loaded on each lane of P1 nuclear fraction "N" (5.1 x 104 cell equivalents), P45 membranes "M" (1.6 x 106 cell equivalents) or S45 cytosol "C" (6.4 x 104 cell equivalents). Anti-Fes antiserum #61 and cellular fractionation have been previously described [62].

 

   Conclusion
Top
 Abstract
 Introduction
 Pattern of Expression
 Fes Function in Myeloid...
 Conclusion
References
 
Over the last several years, clues about the function of c-Fes in normal and neoplastic cells have emerged. Fes has been implicated in cytokine signal transduction, and has been shown, in vitro, to interact with cellular signaling machinery. It is important to note that c-Fes and c-Fps, while similar, are not identical proteins, and the differences between the cellular and viral Fes/Fps proteins are even greater. Thus, it remains to be seen whether recent observations regarding Fps proteins are also applicable to Fes in vivo.

What is known about Fes in myeloid cells is summarized in Figure 3Go. Fes has been shown, by both direct localization and association with cytokine receptors, to reside at the plasma membrane. Upon activation by cytokines, Fes may phosphorylate cytoplasmic targets and participate in a signaling pathway that leads to a cellular response, perhaps differentiation. Alternatively, Fes may translocate to the nucleus upon activation and interact with its targets directly. Fes may also reside permanently in the nucleus and be activated by an as yet unknown signal. Future studies in myeloid cells should further elucidate the role of this kinase in normal and neoplastic myeloid cells.



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  		Fig. 3. Diagram of c-Fes localization and signaling in myeloid cells.

 


   Acknowledgments
 
We thank Wendy Aft for preparing the manuscript and Anne Carlson for helpful discussions. K.E.Y. was a predoctoral trainee supported by USPHS National Institutional Research award CA09056. We wish to acknowledge the support of the Shirley McKernan Cancer Research Endowment, the University of California Tobacco-Related Disease Research Program award 2RT0042 (J.C.G.) and National Institutes of Health award R01CA40163 (J.C.G.).


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 Fes Function in Myeloid...
 Conclusion
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Received July 7, 1995; accepted for publication July 7, 1995.



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