Rho proteins are centralsignaling nodes that function to transduce extracellular signals to facilitatemany intracellular processes. Rho family proteins are Ras-related small GTPasesthat regulate cytoskeletal organization and dynamics, cell adhesion, cell polarity,motility, trafficking, proliferation and survival. Misregulation of Rhoproteins can result in defects in cell morphology, cell migration, andproliferation. Importantly, misregulation of Rho GTPases results in a varietyof disease states. These proteins function as tightly regulated molecularswitches, cycling between an active GTP-bound state and an inactive GDP-boundstate. Because Rho GTPases are aberrantly regulated in disease, it is ofinterest to discover and develop new drugs that target these proteins. In orderto design drugs that are more effective against human disease, it is also ofutmost importance to understand the basic physiological mechanisms that governthe regulation and cell-signaling patterns of these small GTPases.

Using C. elegans asa model organism, I can easily identify pathways that involve Rho GTPases. Oneof the reasons I use C. elegans is because this model organism is easilyamenable to flexible research projects for undergraduate, graduate and medicalstudents. Furthermore, C. elegans has been used in the past to identifyGTPase signaling pathways that are involved in a wide variety of signalingevents, the most notable example being Ras. Additionally, C. elegans cangrow in liquid culture, making them a candidate system for high-throughput drugscreenings. Drugs can also be added to their food and to the plates they aregrown on for more refined analyses for drug target validation andidentification of drug mechanism(s). Hits found in the drug screen can befurther validated in cell culture and/or other in vivo model systems.

As a postdoctoralresearcher, I study how atypical Rho GTPases regulate neuronal outgrowth andmigration. At present, these atypical Rho GTPases are largely uncharacterized.However, there is evidence to suggest that these atypical Rho GTPases areinvolved in cancer and bone turnover. In my postdoc, I also study CDC- 42, awell-characterized Rho GTPase. CDC-42 has been implicated in control of the cellcycle, cell polarity and tumorigenesis. Because CDC-42 is aberrantly regulatedin cancer, I hope to uncover novel inhibitors of the CDC-42 pathway using C.elegans as an "in vivo" test tube.

I also study the normaland pathogenic role of atypical Rho GTPases in C. elegans and in cell culture. C. elegans hastwo Cdc-42 related proteins, chw-1 and crp-1, which remainlargely uncharacterized. chw- 1(Chp/Wrch-1) encodes a protein thatresembles human Chp (Wrch-2/RhoV) and Wrch-1 (RhoU). crp-1 encodes for aprotein that resembles TC10 and TCL. Evidence in other systems and part of mygraduate research suggests that these atypical Rho GTPases are involved incellular signaling, tumorigenesis, metastasis and bone turnover. Research inthe field is finding that these atypical GTPases are regulated differently fromtheir canonical counterparts. For example, EGFR activation results in theactivation of Ras. However, work from myself and others has shown thatactivation of EGFR also results in GDP-bound and inactive Wrch-1, an atypicalGTPase related to CHW-1. Furthermore, while these atypical GTPases share someeffectors with canonical GTPases, they also interact with unique effectors andperhaps drive unique biological processes. To address this discrepancy and tocharacterize these atypical small GTPases, I plan to analyze the normal andpathological roles of these proteins.

Stevens EV, Banet N, Onesto C, Plachco A, Alan, JK, Nikolaishvili-Feinberg N, Midkiff BR,Kuan PF, Liu J, Miller CR, Vigil D, Graves LM, and Der CJ. RhoGDI2 Antagonizes OvarianCarcinoma Growth, Invasion and Metastasis. 2011 Jul;2(4):202-210. Epub 2011 Jul 1. SmallGTPases.

Beazely MA, Alan JK, Watts VS. Activation of Raf-1 by multiple signaling pathways increasesAC6 activation in intact cells. Mol Pharmacol. 2005 Jan;67(1):250-9.

Brady DC, Alan JK, and Cox AD. (2009) Rho GTPases in regulation of cancer cell motility,Invasion, and microenvironment. Cancer Genome and the Tumor Microenvironment. Thomas-Tikhonenko, A (ed.). Springer, NY, pp. 67-92.