Ras and Rap1: A tale of two GTPases.

Ras oncoproteins play pivotal roles in both the development and maintenance of many tumor types. Unfortunately, these proteins are difficult to directly target using traditional pharmacological strategies, in part due to their lack of obvious binding pockets or allosteric sites. This obstacle has driven a considerable amount of research into pursuing alternative ways to effectively inhibit Ras, examples of which include inducing mislocalization to prevent Ras maturation and inactivating downstream proteins in Ras-driven signaling pathways. Ras proteins are archetypes of a superfamily of small GTPases that play specific roles in the regulation of many cellular processes, including vesicle trafficking, nuclear transport, cytoskeletal rearrangement, and cell cycle progression. Several other superfamily members have also been linked to the control of normal and cancer cell growth and survival. For example, Rap1 has high sequence similarity to Ras, has overlapping binding partners, and has been demonstrated to both oppose and mimic Ras-driven cancer phenotypes. Rap1 plays an important role in cell adhesion and integrin function in a variety of cell types. Mechanistically, Ras and Rap1 cooperate to initiate and sustain ERK signaling, which is activated in many malignancies and is the target of successful therapeutics. Here we review the role activated Rap1 in ERK signaling and other downstream pathways to promote invasion and cell migration and metastasis in various cancer types.