Functional diversity in the RAS subfamily of small GTPases

RAS small GTPases regulate important signalling pathways and are notorious drivers of cancer development and progression. While most research to date has focused on understanding and addressing the oncogenic potential of three RAS oncogenes: HRAS, KRAS, and NRAS; the full RAS subfamily is composed of 35 related GTPases with diverse cellular functions. Most remain deeply understudied despite strong evolutionary conservation. Here, we highlight a group of 17 poorly characterized RAS GTPases that are frequently down-regulated in cancer and evidence suggests may function not as oncogenes, but as tumour suppressors. These GTPases remain largely enigmatic in terms of their cellular function, regulation, and interaction with effector proteins. They cluster within two families we designate as 'distal-RAS' (D-RAS; comprised of DIRAS, RASD, and RASL10) and 'CaaX-Less RAS' (CL-RAS; comprised of RGK, NKIRAS, RERG, and RASL11/12 GTPases). Evidence of a tumour suppressive role for many of these GTPases supports the premise that RAS subfamily proteins may collectively regulate cellular proliferation.

Automated summary

RAS small GTPases are important signaling regulators in cancer development. While most research has focused on three well-known oncogenes (HRAS, KRAS, and NRAS), the full RAS subfamily consists of 35 related GTPases with diverse functions. In this study, we highlight a poorly characterized group of 17 RAS GTPases that are down-regulated in cancer and may function as tumor suppressors. These GTPases are clustered into two families, 'distal-RAS' (D-RAS) and 'CaaX-Less RAS' (CL-RAS), and their roles in cellular function, regulation, and interaction with effector proteins remain largely unknown. The evidence suggests that these GTPases may collectively regulate cellular proliferation.