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Autoregulation of c-Fes by intramolecular interaction of the F-BAR and SH2 domains: a novel role for the unique N-terminal region

The c-Fes protein is a structurally unique non-receptor protein-tyrosine kinase encoded by the fes/fps proto-oncogene and is expressed in myeloid hematopoietic, vascular endothelial, and some epithelial and neuronal cell types. Downstream of a number of cytokines and growth factors, c-Fes plays a role in regulation of cell growth, differentiation, and chemotaxis. Dysregulation of c-Fes activity is implicated in a number of cancers, including acute myelogenous leukemia (AML) and some renal carcinomas. Structurally, c-Fes includes an amino-terminal F-BAR region—consisting of a Fes/CIP4 homology (FCH) domain and the first of two coiled-coil motifs (CC1)—followed by CC2 and the carboxy-terminal Src homology 2 (SH2) domain closely linked to a typical bilobate kinase domain (KD). 
Unlike its oncogenic retroviral orthologs (v-Fes/Fps), c-Fes kinase activity is tightly regulated in vivo, yet lacks known negative regulatory features common to other cytoplasmic tyrosine kinases, such as a SH3 domain or regulatory tail tyrosine. In fact, a c-Fes truncation containing only the SH2 and KD is constitutively active which suggests a possible auto-inhibitory role for the unique N-terminal region. Deletion and mutation experiments reveal that loss of the predicted CC1 structure leads to upregulation similar to the c-Fes SH2-KD truncation. This would be the first case of autoinhibition by the coiled-coil; however, it is still unclear how the F-BAR acts in cis to accomplish autoinhibition. Substitution of the native c-Fes SH2 with that of v-Src (but not homologous v-Fps) displays an uninhibited catalytic activity level analogous to the CC1 mutant, suggesting interdomain interaction between the F-BAR and SH2/KD may contribute to an inactive conformation. I collected evidence for this mechanism and began to develop tools to define the putative F-BAR:SH2 interface utilizing the bimolecular fluorescence complementation (BiFC) technique. Demonstrated by BiFC in 293T cells, the F-BAR interacts with the SH2 domain in a CC1-dependent manner. It may be that CC1 forms a critical interface with αB of the SH2 as preliminary data suggest that v-Src-mimetic mutations in αB weaken CC1-SH2 recognition. Further characterization of the specific intramolecular interactions involved in c-Fes regulation would advance new paradigms in modular domain relationships and could expand cancer drug discovery efforts.