The Rho family of GTPases is a family of proteins that couples extracellular signaling events to changes in cellular function including endocytosis. The Rho family is comprised of at least fifteen members and their isoforms including: Rho subfamily (A, B, C isoforms), Rac subfamily (1, 2, 3 isoforms), Cdc42 (Cdc42Hs and G25K splice variants), Chp, Rnd subfamily (Rnd1, Rnd2, Rnd3 isoforms), RhoD, RhoG, RhoH, and TC10. Rho family members, like all GTPases, cycle between an inactive GDP-bound state and an active GTP-bound state. The activity of Rho GTPases is modulated by several accessory proteins including guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and GDP dissociation inhibitors (GDIs). GEFs, as their name implies, stimulate Rho family members to exchange GDP for GTP; GTPase activation is the result. GAPs stimulate the Rho GTPase to hydrolyze its bound GTP, returning the Rho protein to its inactive GDP-bound state. GDIs preferentially bind Rho-GDP and modulate the activation and targeting of Rho-GDP to the membrane. Upon activation, Rho GTPases interact with a plethora of downstream effector molecules that, in turn, modulate cellular function.

It was initially observed that Rho family members regulate the formation of specialized actin structures. It is now known that they also control diverse cellular events including transcription, cell growth, development, progression through the cell cycle and exocytosis. There is increasing evidence that Rho family members also regulate multiple forms of internalization including phagocytosis, macropinocytosis, clathrin-dependent and clathrin-independent endocytosis. We have observed that RhoA and Rac1 regulate endocytosis at the apical and basolateral poles of MDCK cells. These GTPases may also play a role in regulating postendocytic traffic. We are currently exploring the downstream effector pathways involved in Rho family-mediated regulation of endocytic traffic. Moreover, we are exploring the role of RhoB in polarized endocytic traffic. This GTPase is found associated with endosomes and apparently regulates their function.

Current projects in the laboratory include:

I. Analysis of endocytic pathways in polarized MDCK cells
II Regulation of endocytic traffic by Rho family GTPases
III. Stretch-regulated endocytosis/exocytosis in bladder uroepithelium