Forkhead proteins, members of the winged helix family of transcription factors, have been implicated in a multitude of biological processes. According to conventional views, mammalian forkhead proteins are death-promoting/cell cycle arrest factors whose function must be inhibited to ensure cell survival and growth. In the absence of serum or growth factors, forkhead is dephosphorylated and localized in the nucleus, where it activates proapoptotic and/or antigrowth/cell cycle genes including p27 kinase inhibitor protein (p27kip1), Bcl-2–interacting mediator of cell death (Bim), Fas ligand (FasL), growth-arrest and DNA damage inducible gene 45A (GADD45A), and B-cell translocation gene (BTG)-1. Serum or growth factor signaling results in phosphoinositide 3-kinase (PI3K)/Akt-dependent phosphorylation and nuclear translocation of forkhead proteins, with subsequent cell survival and/or proliferation.

Recent studies suggest that this model of mammalian forkhead function is overly simplistic. In addition to their role in promoting cell death and cell cycle arrest, forkhead proteins play a critical role in mediating embryonic angiogenesis, cell differentiation, metabolism, redox state, and immunity.

Most of our current knowledge about forkhead function is derived from studies in the fruit fly (Drosophila melanogaster), roundworm (Caenorhabditis elegans), and nonendothelial mammalian cell types. In the first part of this chapter, we draw on this extensive literature to review the complex signaling mechanisms underlying forkhead regulation of metabolism, survival, proliferation, longevity, and tumorigenesis. In the second part, we discuss more recent evidence implicating a role for forkhead proteins in endothelial cell (EC) biology.

FROM FRUIT FLY TO HUMAN

The name forkhead was first derived in 1989 from a homeotic gene (fkh) that encodes a nuclear protein involved in the development of the terminal regions of the Drosophila melanogaster embryo (1).