The c-Fes Family of Protein-Tyrosine Kinases

Abstract

The human c-fes protooncogene encodes a protein-tyrosine kinase (c-Fes) distinct from c-Src, c-Abl and other nonreceptor tyrosine kinases. Although originally identified as the cellular homolog of several transforming retroviral oncoproteins, Fes was later found to exhibit strong expression in myeloid hematopoietic cells and to play a direct role in their differentiation. Recent work has shown that Fes exhibits a more widespread expression pattern in both developing and adult tissues, suggesting a general physiological function for this kinase and its closely related homolog, Fer. This review highlights the unique aspects of Fes structure, regulation, and function that set it apart from other tyrosine kinase families.

FES kinases are required for oncogenic FLT3 signaling

“…9 FES and FER (FES-related protein) constitute a distinct sub-family of non-receptor tyrosine kinases. 10 Below, we will refer to FES and FER collectively as FES kinases.…”

Requirement of the coiled-coil domains of p92c-Fes for nuclear localization in myeloid cells upon induction of differentiation

“…It follows that both the coiled-coil domains are necessary for Fes to translocate and that they must be in a specific spatial conformation, since the removal of the portion of p92 cFes between the two coiled-coil domains (D7D11) impairs the translocation. To check whether p92 c-Fes oligomerization (Read et al, 1997;Smithgall et al, 1998;Cheng et al, 1999) is somehow related to the event of nuclear translocation we performed Western blot experiments on HL60 cells overexpressing c-Fes and on K562 cells expressing mutants missing CC1 and CC2. These experiments showed that Fes oligomers are localized in the nucleus and that the deletion of the coiled-coil domains prevents both oligomerization and nuclear translocation, thus confirming the key role of the coiledcoil domains in this process.…”

“…Considering that exon 7 encodes a portion of p92 c-Fes located between the two coiled-coil domains, that the process of nuclear translocation probably deals with Fes activation and that evidence exists in literature that CC1 and CC2 are invloved in Fes activation (Read et al, 1997;Cheng et al, 1999;Smithgall et al, 1998), we investigated whether the coiled-coil domains of p92 c-Fes have a role in the process of nuclear translocation. The recombinant constructs encoding the aminoterminal domain of c-Fes and its deleted forms are shown in We treated these cells with the differentiation-inducing agents and checked them at confocal microscopy.…”

“…The experiment shows that the proteins expressed by a construct missing the CC1 or the CC2 domain are not able to translocate to the nucleus, while the constructs expressing the whole protein or the N-terminal domain are present in the nucleus. coiled-coil domains and that it has been hypothesized that the oligomers are the active form of p92 c-Fes (Read et al, 1997;Smithgall et al, 1998;Cheng et al, 1999), we investigated whether oligomerization is a cytoplasmic or a nuclear event and whether it is required for translocation. To do so, we treated HL60-FLAG-FES cells with the crosslinking agent BS3 and we checked the formation of oligomers in cytoplasmic and nuclear extracts.…”

“…Other reports indicate that cytokine engagement of the IL-4 receptor leads to phosphorylation of p92 c-Fes (Izuhara et al, 1994) and that p92 c-Fes recognizes and phosphorylates a p130 and a p75 in a colony stimulating factor-1 (CSF-1)-dependent macrophage cell line (Areces et al, 1994). Other possible c-Fes interactions are summarized in literature (Ferrari et al, 1995;Smithgall et al, 1998;Greer, 2002). Gene targeting experiments in mice have demonstrated that myelopoiesis is not substantially affected by the lack of c-Fes activity or c-Fes (Hackenmiller et al, 2000;Zirngibl et al, 2002).…”