Rac and Rho

Abstract

What are they? Rac and Rho are members of the Ras superfamily of small GTPases, along with the Rabs, Rans, Raps, Rals, and so on. Not to be confused with… Rho, the transcription terminator in prokaryotes, or Rho, the subunit of the GABA receptor, or Rac, the serine/threonine kinase (also called Akt/PKB). How were they discovered? The first Rho gene was discovered by mistake, in 1985, by a group trying to clone a homologue of the α subunit of human chorionic gonadotropin from the sea snail Aplysia. Using the Aplysia Rho sequence, three closely related mammalian genes were cloned, now called RhoA, RhoB and RhoC. Rac was first identified as a substrate for the C3 transferase that modifies Rho (although, in fact, the transferase acts on Rac only inefficiently). There are three mammalian types of Rac: Rac1, Rac2 and Rac3 (sometimes called Rac1B). Do they have any relatives? Lots, mostly with confusing, unmemorable or inappropriate names. Several of them are called Rho (RhoD, RhoE and RhoG) even though they are no more closely related to the original Rho than they are to Rac. What about RhoF, you may ask? Not yet discovered. To confuse matters further, RhoE was re-cloned and renamed Rnd3 well after its sequence was first published. Look out for other family members, such as Cdc42, TTF and TC10, whose names do not conform to the R∗∗ tag that identifies other Ras superfamily members. Why are Rac'n'Rho often mentioned in the same breath? Well, Rac'n'Cdc42 doesn't really trip off the tongue, does it? It might also have something to do with the simultaneous publication in 1992 of two Cell papers describing the functions of Rac and Rho. Where are they found? Homologues of Rho and Rac have been identified in all eukaryotes where anyone has bothered to look, including yeasts, worms, insects, plants and mammals (even camels). But they have not so far been found in prokaryotes. What do they do? Rac and Rho coordinate signal transduction, in league with Ras. Their initial claim to fame was that they regulate actin cytoskeletal organization, but as soon as biologists started investigating the contribution of Rho and/or Rac to their own favourite assays, it became apparent that they are involved in vesicle transport, secretion, phagocytosis, neurite outgrowth, regulation of MAP kinase cascades, activation of transcription factors, apoptosis… Even the cell cycle community eventually awakened to their importance. If you want to avoid Rac and Rho, stick to prokaryotes. How do they work? Like all GTPases, they cycle between a GTP-bound and a GDP-bound form. Dogma has it that they are ‘active’ in the GTP-bound form and ‘inactive’ in the GDP-bound form. Thus, incoming signals should stimulate an increase in the level of the GTP-bound form. Although this was believed to be true for a long time, it has only recently been proved formally. The conformation of Rac and Rho is different when bound to GTP than when bound to GDP, and in the GTP-bound conformation they can interact with downstream targets and thereby induce cellular responses. Who are their known associates? A multitude of directly interacting targets have been identified, including protein kinases (for example, PAKs and Rho-kinases) and a whole range of ‘adaptor’ proteins (for example, POR1 and IQGAP), so-called because they bring together other proteins. Even tubulin can be made to interact with Rac. What all these targets do, and how their activity is altered by Rho and Rac, is the subject of feverish investigation. Do we need them? We don't know yet. Rac2 knockout mice have no major defects, but this is not surprising as Rac2 is specifically expressed only in haematopoetic cells. Other Rho and Rac knockout mice are still in the pipeline. Do they have commercial potential? A Rho-kinase inhibitor made headlines recently, not only for lowering blood pressure in rats with hypertension but also for inhibiting invasion of cancer cells in an animal model. Activation of Rac can either enhance or inhibit invasion of cancer cells, depending on the cell type and the conditions. So, there is certainly therapeutic potential in developing inhibitors and/or activators of Rho and Rac signalling. A Ridley, Ludwig Institute for Cancer Research, University College London Branch, 91 Riding House Street, London W1P 8BT, UK.