Myosin and its Isoforms: Aspects of Migration and Evolution

The current issue of Journal of Cell Biology has an article out on the Regulation of protrusion, adhesion dynamics, and polarity by myosins IIA and IIB in migrating cells. Myosin II functions as a molecular motor which facilitates contraction of the actin cytoskeleton during migration, resides outside of protrusions at the front of motile cells, and acts at a distance to impact cell protrusion, signaling, and maturation of nascent adhesions. So clearly myosin II is a protein that is of great importance for understanding cell migration.

But Myosin II is not just one protein. There are actually two isoforms of this protein that are not identical, just very very similar. I’m not familiar with where in the natural history of cells the genes for these two proteins diverged, but they’re clearly derived from a single ancestral gene. And beyond that, there are quite a few other myosins which are more distantly similar (the list easily goes into double-digits).

Vicente-Manzanares et al., in their paper, determine the divergent functions of myosin IIA (MIIA) and MIIB, and find that these isoforms have become suited to spatial and functional niches within the cell. They found:

MIIA controls the dynamics and size of adhesions in central regions of the cell and contributes to retraction and adhesion disassembly at the rear. In contrast, MIIB establishes front–back polarity and centrosome, Golgi, and nuclear orientation.

That’s an interesting finding – and not just for those migration afficionados who are interested in MII for MII’s sake. The duplication of genes, divergence, neofunctionalization, and niche establishment, is a theme that is occurring frequently in the cell biology literature. As we begin to understand the roles of Src tyrosine kinase, PI-3 Kinase, Rho and Rac small GTPases, and so on (just to stick within the realm of proteins that I’m most familiar with), we begin to look at the roles of Src family members Src/Fyn/Yes, a half dozen PI-3 Kinase isoforms, RhoA-through-G, Rac1-through-3, etc.

Sure, it’s complicated, which is why it’s easier for us to observe and characterize themes in signal transduction in cell biology, as we gradually expand our knowledge base.

Some of my impressions, however:

1. The enclosed environment of the cell is, in essence, just a sac of a few million proteins, and billions of different protein-protein interactions. Each protein-protein interaction exhibits some form of bias, creating some sort of assymetry (either in the form of chemical reactions, spatial response/regulation to other factors, or reation/interaction rates).
2. Patterns of interactions lead to patterns of biases or chemistries, which lead to patterns of phenotypes. All of this is controlled by various levels of gene expression control.
3. Just as in vertebrates and other animals, we see considerable variation from organism to organism, and even from cell to cell in a single organism. We also see vestigial, highly specialized, “opportunistic,” divergent, and convergent genes/proteins. The cell is a veritable jungle of niches that are new, old; empty, filled, or unneeded.
4. We also see many balances of opposing activities in cell biology where polar asymmetries exist (e.g. PI-3K and PTEN/SHIP-1; Rac/Cdc42 and Rho; G12 and G13; etc.).

In the words of Theo Dobzhansky, nothing in biology makes sense except in the light of evolution.

References:

• Vicente-Manzanares M, Zareno J, Whitmore L, Choi CK, and Horwitz AF. Regulation of protrusion, adhesion dynamics, and polarity by myosins IIA and IIB in migrating cells. J. Cell Biol 2007, 176 (5):573-580. JCB
• Sellers JR. Myosins: a diverse superfamily. Biochim Biophys Acta. 2000 Mar 17;1496(1):3-22. Pubmed
• Segawa Y, Suga H, Iwabe N, Oneyama C, Akagi T, Miyata T, Okada M. Functional development of Src tyrosine kinases during evolution from a unicellular ancestor to multicellular animals. Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12021-6. Pubmed
• Rommel C, Camps M, Ji H. PI3Kdelta and PI3Kgamma: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol. 2007 Mar;7(3):191-201. Pubmed
• Boureux A, Vignal E, Faure S, Fort P. Evolution of the Rho family of ras-like GTPases in eukaryotes. Mol Biol Evol. 2007 Jan;24(1):203-16. Pubmed