Non-canonical and constitutive activation of small GTPases: more than an exception to the rule?

The superfamily of small GTPases comprises over 150 members, clustered in different families (e.g., Ras, Rab, Rho), that together are essential for a wide range of cellular functions. Most GTPases behave as molecular on/off switches, with regulatory proteins controlling their cycling between the GDP-bound, inactive form and the GTP-bound, active form. However, there is a substantial number of small GTPases that do not adhere to this canonical mode of regulation. This can result from key sequence differences that maintain these GTPases mostly in the GTP-bound form. Alternatively, specific post-translational modifications, including ubiquitination or alternative lipidation, can activate these GTPases, for example, due to interference with their intrinsic GTP hydrolysis capacity. Such 'atypical' GTPases are often constitutively active and are furthermore characterized by fast turnover. Consequently, their output is much more a function of their expression levels, with proteasomal or lysosomal degradation limiting their signaling capacity. This review discusses recent insights into non-canonical activation of small GTPases. We also discuss modifications, in particular palmitoylation, which allows otherwise canonical GTPases to become (constitutively) active, escaping their usual regulatory mechanisms. Finally, we discuss the potential biological importance of non-canonical GTPase regulation. We focus on the difference in kinetics and signal duration between canonical cycling versus non-canonical activation, and discuss differences related to fast, external stimulation (e.g., by hormones and growth factors) versus slow, intrinsic signaling, linked to altered metabolism, autophagy, or disease.