RAL GTPases: Biology and Potential as Therapeutic Targets in Cancer

Abstract

More than a hundred proteins comprise the RAS superfamily of small GTPases. This family can be divided into RAS, RHO, RAB, RAN, ARF, and RAD subfamilies, with each shown to play distinct roles in human cells in both health and disease. The RAS subfamily has a well-established role in human cancer with the three genes, ,, and being the commonly mutated in tumors. These mutations, most often functionally activating, are especially common in pancreatic, lung, and colorectal cancers. Efforts to inhibit RAS and related GTPases have produced inhibitors targeting the downstream effectors of RAS signaling, including inhibitors of the RAF-mitogen-activated protein kinase/extracellular signal-related kinase (ERK)-ERK kinase pathway and the phosphoinositide-3-kinase-AKT-mTOR kinase pathway. A third effector arm of RAS signaling, mediated by RAL (RAS like) has emerged in recent years as a critical driver of RAS oncogenic signaling and has not been targeted until recently. RAL belongs to the RAS branch of the RAS superfamily and shares a high structural similarity with RAS. In human cells, there are two genes, and, both of which have been shown to play roles in the proliferation, survival, and metastasis of a variety of human cancers, including lung, colon, pancreatic, prostate, skin, and bladder cancers. In this review, we summarize the latest knowledge of RAL in the context of human cancer and the recent advancements in the development of cancer therapeutics targeting RAL small GTPases.

Rala and the exocyst control Pvr trafficking and signaling to ensure lymph gland homeostasis inDrosophila melanogaster

“…Depletion or deletion of RalA/B in cell lines and in mice reduced cancer-relevant processes, such as anchorage-independent growth, metastasis and invasion of several cancer types. These cancer-promoting effects of RalA/B have been linked to both Rlip/RalBP1 and the exocyst in a manner that depends on the Ral isoform and the cancer type (Yan & Theodorescu, 2018). Components of the exocyst have been found to be upregulated in certain cancer types and to affect cancer-relevant cell biology dependent or independent of Ral proteins (Tanaka, Goto, & Iino, 2017).…”

Targeting the Small GTPase Superfamily through Their Regulatory Proteins

“…[35] TheRal (Ras-like) proteins,asubset of the Ras subfamily, have emerged as critical targets in cancer therapy. [36] 500 000 compounds were screened in silico in ap ocket identified in RalA-GDP that is not present in the RalA or BG NP structure. [37] It was anticipated that compounds binding in this pocket would prevent the activation of the Ral GTPases by their GEFs.8 8c ompounds were tested in two cell-based assays;R BC6 and RBC8 (11 and 12,F igure 9) were chosen for their ability to reduce RalA activation in cells,and binding in the desired pocket was confirmed by NMR spectroscopy.…”

Targeting der kleinen GTPasen über ihre regulatorischen Proteine

“…[35] Die Ral-Proteine ("Ras-like"), eine Untergruppe der Ras-Subfamilie,h aben sich als kritische Targets in der Krebstherapie herausgestellt. [36] 500 000 Verbindungen wurden in silico in einer Tasche gescreent, die in RalA-GDP identifiziert wurde und in der RalA oder BG NP-Struktur nicht vorhanden ist. [37] Es wurde erwartet, dass Verbindungen, die in diese Tasche binden, die Aktivierung der Ral GTPasen durch ihre GEFs verhindern würden.…”