When I started my laboratory at Caltech in 1987, I hung on my door a wall chart from Oncogene Sciences with all the known proto-oncogenes and their cellular locations and regulatory relationships. One of these, ras, was identified by viral and cancer genetics as a dominant oncogene in many tumors and in transforming retroviruses. The RAS protein is a small GTPase, which undergoes a cycle of guanine nucleotide exchange and hydrolysis. RAS was known to be active when bound to GTP, but its normal role in the cell was not known, nor was how it became activated and what it did once it was. RAS and epidermal growth factor receptor (EGFR) resided on opposite sides of the wall chart. The molecular genetics of Caenorhabditis elegans vulval development allowed us to draw a big arrow between RAS and EGFR in 1990 and other arrows in 1992. The intellectual pathway to RAS is a genetic story, the highlight being 15 years ago when we described the initial genetic pathway from a cell surface receptor to the ras proto-oncogene let-60 in C. elegans (Han et al. 1990). This article places this genetic analysis in perspective.

© 2006 by the Genetics Society of America. I thank Bob Horvitz for showing me my first C. elegans cell division and for his generosity when I returned as a ''ghost'' to work on the vulva. I especially thank my many colleagues for making the pathway to RAS so exhilarating, productive, and fun.

<p>Published - <a href="/records/g6kwr-58m76/files/GEN1722727.pdf?download=1">GEN1722727.pdf</a></p>