Ras and Rap1: A tale of two GTPases

Abstract

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.

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

“…RAP1 (Ras-related protein 1) signalling pathway was identified as enriched in deiminated proteins in whole bovine serum. It belongs to a superfamily of small GTPases, with pleiotrophic regulatory functions in cellular processes, such as nuclear transport, cell cycle progression, vesicle trafficking, cell adhesion and cytoskeletal rearrangement [217]. Rap1 is an inflammatory regulator, is highly expressed in platelets and is a key molecule for platelet activation and adhesion in injury [218,219].…”

Whole‐genome analysis uncovers recurrent IKZF1 inactivation and aberrant cell adhesion in blastic plasmacytoid dendritic cell neoplasm

“…Hence, IKZF1 deficiency in BPDCN might underlie or contribute to the observed overactivation of the PI‐3‐K/Akt pathway. In contrast, the Rap1 pathway regulates cell motility and integrin‐mediated adhesion in leukocytes, lymphocytes and dendritic cells, both of which are processes hijacked by neoplastic cells to disseminate to other body sites . In fact, activation of Rap1 signaling has been shown to trigger migration of T‐acute lymphoblastic leukemia and B‐cell lymphoma cells, in vitro and in vivo, respectively …”

“…Although the incidence of CNAs involving IKZF1 was lower in the extension cohort compared to the sequenced cohort (difference not statistically significant, P > .05, Fisher's exact test), patients with normal IKZF1 copy number might still carry inactivating balanced to disseminate to other body sites. 51 In fact, activation of Rap1 signaling has been shown to trigger migration of T-acute lymphoblastic leukemia and B-cell lymphoma cells, in vitro and in vivo, respectively. 52,53 We found that genes silenced by PRC2 (EZH2) were the most over- Table S16 for a complete list of enriched terms/ processes).…”

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

“…Similarly, here we showed that altered levels of human Rap1a impacted the migration speed of GBM CSCs. Accumulating evidence indicates a general role for Rap1a in the cell migration and invasion of a variety of tumors 64,66 . Depending on the cancer, either elevated or decreased Rap1a activity enhances or suppresses tumor invasion, typically through regulation of either cadherinor integrin-based adhesions 66 .…”

“…Accumulating evidence indicates a general role for Rap1a in the cell migration and invasion of a variety of tumors 64,66 . Depending on the cancer, either elevated or decreased Rap1a activity enhances or suppresses tumor invasion, typically through regulation of either cadherinor integrin-based adhesions 66 . This suggests complex roles for Rap1a and the downstream molecular pathways and effectors, which likely depend on the tumor type and cellular context 64 .…”