Prohibitin: a potential therapeutic target in tyrosine kinase signaling

Abstract

Prohibitin is a pleiotropic protein that has roles in fundamental cellular processes, such as cellular proliferation and mitochondrial housekeeping, and in cell- or tissue-specific functions, such as adipogenesis and immune cell functions. The different functions of prohibitin are mediated by its cell compartment-specific attributes, which include acting as an adaptor molecule in membrane signaling, a scaffolding protein in mitochondria, and a transcriptional co-regulator in the nucleus. However, the precise relationship between its distinct cellular localization and diverse functions remain largely unknown. Accumulating evidence suggests that the phosphorylation of prohibitin plays a role in a number of cell signaling pathways and in intracellular trafficking. Herein, we discuss the known and potential importance of the site-specific phosphorylation of prohibitin in regulating these features. We will discuss this in the context of new evidence from tissue-specific transgenic mouse models of prohibitin, including a mutant prohibitin lacking a crucial tyrosine phosphorylation site. We conclude with the opinion that prohibitin can be used as a potential target for tyrosine kinase signal transduction-targeting therapy, including in insulin, growth factors, and immune signaling pathways.

Figure 1

A schematic diagram showing the location of known phosphorylation sites in different structural domains in PHB1. The conserved phosphorylation sites in PHB2 are shown in red. S, serine; T, threonine; Y, tyrosine.

Figure 2

A schematic diagram showing known and potential crosstalk between tyrosine phosphorylation and serine/threonine phosphorylation or O-GlcNAc modification in PHB1. The phosphorylation of PHB at Tyr-114 is known to have a priming effect on the phosphorylation at Tyr-259 and Tyr-249 residues. Ser, serine; Thr, threonine; Tyr, tyrosine; g -O-GlcNAc modified; p, phosphorylated.

Figure 3

A schematic diagram showing the relationship among various posttranslational modifications of PHB1 and their relevance to the regulation of PHB1 functions and cell signaling events. Additionally, phosphorylation of PHB1 appears to be involved in the intracellular trafficking of PHB1 (not shown).

Figure 4

Does tyrosine phosphorylation of PHB1 plays a role in its iron binding function or potentially in other mitochondrial attributes of PHB1? A schematic diagram showing a potential role of the phosphorylation of PHB1 at tyrosine (for example, Y114) residue(s) in the iron binding function of PHB. This may be because a number of tyrosine kinases (for example, the RTK and Src family kinases) that phosphorylate PHB are known to localize to the mitochondria. RTK -receptor tyrosine kinase; p -phosphorylated; Y—tyrosine.