RASSF5

RASSF5 Full Name

Ras association (RalGDS/AF-6) domain family member 5

RASSF5 Introduction

RASSF5, also widely known as NORE1 (Novel Ras Effector 1), has emerged as an important tumor suppressor and signaling scaffold protein in modern cancer biology. Located on chromosome 1q32.1, RASSF5 belongs to the RASSF family and is uniquely characterized by the presence of both a Ras-association domain and a SARAH domain, enabling it to connect Ras signaling with Hippo pathway regulation. Unlike classical enzymes or kinases, RASSF5 primarily functions as a molecular adaptor that organizes multi-protein signaling complexes controlling apoptosis, cell-cycle arrest, senescence, and cytoskeletal stability. This feature makes RASSF5 particularly valuable for researchers investigating why malignant cells evade programmed cell death and continue uncontrolled proliferation. Increasing evidence shows that RASSF5 expression is frequently silenced in human cancers through CpG island promoter hypermethylation, positioning it as a clinically relevant epigenetic biomarker and a potential target for precision oncology strategies.

From a mechanistic perspective, RASSF5 plays a central role in regulating the Hippo signaling cascade through direct interaction with MST1/2 kinases via its SARAH domain. By activating MST1/2, RASSF5 contributes to downstream suppression of YAP/TAZ-TEAD transcriptional activity, a pathway strongly associated with tumor growth, metastasis, stemness, and therapeutic resistance. Recent reviews focusing on Hippo pathway biology have highlighted RASSF5 as one of the best-characterized members of the RASSF family because of its ability to integrate Ras-driven oncogenic signals with growth-inhibitory pathways. In addition to Hippo signaling, RASSF5 is linked to AKT, ERK, RAC1, and MLK3 regulatory networks, allowing it to influence inflammation, oxidative stress responses, and mitochondrial apoptosis. These multifunctional properties are especially important for scientists developing targeted therapies aimed at restoring apoptosis sensitivity in resistant tumor cells. Emerging epigenetic studies further suggest that reactivation of silenced RASSF5 through DNA methylation-targeting therapies may offer a promising approach for overcoming tumor progression and drug resistance.

Beyond oncology, RASSF5 is increasingly recognized for its involvement in degenerative and inflammatory diseases, particularly intervertebral disc degeneration (IDD). Recent investigations into extracellular vesicle and microRNA-based regenerative therapies have identified RASSF5 as a key downstream signaling target involved in apoptosis regulation and tissue homeostasis. Several miRNAs, including miR-142-3P, miR-532, miR-21, and miR-27a-3p, have been reported to modulate RASSF5-associated pathways, thereby influencing nucleus pulposus cell survival, inflammatory signaling, and extracellular matrix remodeling. Experimental findings suggest that dysregulated RASSF5 signaling may accelerate degenerative processes through aberrant MST1/LATS1 and RAS/RAC1 pathway activity, while controlled modulation of RASSF5 could support anti-inflammatory and regenerative effects. As researchers continue exploring Hippo pathway therapeutics, epigenetic medicines, and RNA-based interventions, RASSF5 is gaining attention not only as a cancer suppressor gene but also as a broader regulator of cell fate decisions with translational relevance across oncology, regenerative medicine, and molecular therapeutics.

Alternate Names for RASSF5

RASSF5; Ras association (RalGDS/AF-6) domain family member 5; RAPL; Maxp1; NORE1; NORE1A; NORE1B; RASSF3; ras association domain-containing protein 5; new ras effector 1

• 1.Zhao Y, et al.; New Insights into YAP/TAZ-TEAD-Mediated Gene Regulation and Biological Processes in Cancer. Cancers (Basel). 2023, 15(23):5497.
  2.Yuan C, et al.; Role of MiR-27a-3p in Intervertebral Disc Degeneration through Targeting RASSF5 via MST1/LATS1 and RAS/RAC1 Signaling Pathway. J Healthc Eng. 2022, 2022:4457673.