Posted by: Dan | July 19, 2006

Evolution of Phosphoinositol 3-Kinases in Eukaryotes

Nature Reviews in Genetics has an interesting article out, relevant to both my discussions of the molecular basis for evolution and cell migration: The evolution of phosphatidylinositol 3-kinases (PI3Ks) as regulators of growth and metabolism.

Looking at Class I, II, and III isoforms across the model organisms S. cerevisiae, S. pombe, C. elegans, D. discoideum, D. melanogaster, and mammals, Engelman et al. found an expected correlation between phylogenetic acquisition of some metabolic cellular functions and expansion of this kinase family. For instance, Yeast only have one PI3K isoform, which potentially represents the progenitor the remainder of PI3Ks among eukaryotes: Vps34 (vacuolar protein-sorting defective 34). Vps34 is classified as a Class III PI3K, which all function by marking specific cellular membranes for trafficking events. In addition to vesicle sorting, Class III PI3K’s have been shown to be involved in protein synthesis through mTOR (mammalian Target Of Rapamycin) in higher eukaryotes.

Class I PI3K isoforms, the most well-studied thus far, contribute extensively to chemotaxis, actin rearrangement, cell survival and cell cycle, depending on the cell type and isoform. They are further subdivided into IA and IB subclasses, which are preferrentially regulated by growth factors and G protein-coupled receptors, respectively.

Class II isoforms, still poorly understood, appear to be regulated in still different ways, for different cellular functions.

The overall point of the paper is clear, however – all of the PI3K isoforms appear to have been generated from a common enzyme prototype, based on functional, regulatory, structural and sequence homologies. And from this useful function of vesicle sorting, eukaryotes have evolved a series of isoforms able to take unique regulatory inputs, and generate uniquely phosphorylated phosphoinositides at different specific subcellular locations, to regulate cellular functions at membrane sites throughout the cell.

This diversification from a single enzyme fits extremely well with previous models of evolution of signaling complexity, as put forth most recently on this blog with Modeling Evolution of Protein-DNA Interactions.

References:

  • The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Engelman JA, Luo J, Cantley LC. Nat Rev Genet. 2006 Aug ; 7(8): 606-19. Pubmed.

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