Introduction
C-Raf, also known by its gene name RAF1, is a protein found within human cells that acts as a molecular messenger. It plays a role in cellular communication, transmitting signals from the cell’s outer surface to its inner nucleus. This process guides a cell’s basic decisions, such as whether to grow, survive, or specialize. C-Raf belongs to a family of proteins known as serine/threonine-specific protein kinases.
The Role of C-Raf in Cellular Signaling
C-Raf functions as a kinase, adding phosphate groups to other proteins, acting like an “on” or “off” switch. It is a component of the MAPK/ERK signaling pathway, a cellular communication network. This pathway can be thought of as a relay race, where a signal begins at the cell surface and is passed along a chain of proteins until it reaches the cell’s DNA.
In this relay, C-Raf receives a signal, often initiated by growth factors binding to cell surface receptors. Upon activation, C-Raf phosphorylates and activates MEK1 and MEK2. These MEK proteins, in turn, phosphorylate and activate ERK1 and ERK2, the final kinases in this cascade. Activated ERK proteins then move into the cell nucleus, where they instruct the cell to carry out various processes, including growth, division, and survival.
The Raf kinase family includes two other members, A-Raf and B-Raf. These three isoforms operate similarly and participate in the same MAPK/ERK pathway. Their expression levels can vary in different tissues or under specific conditions. For instance, B-Raf is highly expressed in neuronal tissues, whereas C-Raf and A-Raf are more prevalent in skeletal muscle and bone marrow.
C-Raf and Its Connection to Disease
Genes like RAF1 are proto-oncogenes, meaning they are normal genes that can become cancer-causing oncogenes if altered. When mutations occur in the RAF family, particularly in B-Raf, they can lock the MAPK/ERK signaling pathway in a continuously “on” state. This uncontrolled activation leads to excessive cell growth and division, a hallmark of cancer. While B-Raf mutations, such as the common V600E mutation, are found in approximately 8% of human cancers, including melanoma, C-Raf mutations are much less common, appearing in less than 1% of cancer cell lines.
Despite the rarity of its direct mutations, C-Raf plays a role in cancers where other upstream pathway members, such as RAS, are mutated. RAS mutations are present in about 30% of human cancers, including more than 90% of pancreatic cancers and 30% of lung cancers. In these RAS-mutated cancers, C-Raf often serves as a primary downstream messenger, relaying the oncogenic signal. For example, in mouse models of lung cancer driven by oncogenic KRAS, C-Raf is essential for tumor initiation, while B-Raf is not.
C-Raf’s direct involvement in specific cancers has also been observed. Somatic mutations in CRAF have been identified in non-small cell lung cancer patients, leading to increased ERK pathway activation and promoting anchorage-independent growth. Beyond cancer, germline mutations in genes of the RAS-RAF-MEK-ERK pathway, including RAF1, cause a group of developmental disorders known as “RASopathies.” These syndromes, which include Noonan syndrome, Noonan syndrome with multiple lentigines, and cardio-facio-cutaneous syndrome, are characterized by features like postnatal short stature, neurocognitive delay, and heart defects.
Therapeutic Targeting of the RAF Pathway
Understanding the RAF pathway’s role in cancer has led to the development of targeted therapies, particularly for cancers with mutated RAF proteins. Scientists have created RAF inhibitors, drugs designed to block the activity of these altered proteins. These inhibitors, such as vemurafenib and dabrafenib, have shown effectiveness in treating B-Raf V600E-mutated cancers like melanoma by shutting down ERK activation.
However, targeting the RAF pathway presents complexities and challenges. Paradoxical activation is a phenomenon where some B-Raf inhibitors can unintentionally activate C-Raf, especially in cells with wild-type B-Raf or those with RAS mutations. This occurs because the inhibitor can induce the formation of RAF protein dimers, where a drug-bound RAF protein activates an unbound one. In some cases, this paradoxical activation can worsen the cancer or lead to the development of new tumors, such as cutaneous squamous cell carcinomas or keratoacanthomas.
Targeting C-Raf effectively is a challenge for drug developers, particularly in RAS-mutant cancers where no specific C-Raf inhibitor has yet been approved. Research focuses on developing more precise inhibitors, known as pan-RAF inhibitors or type II RAF inhibitors, that can inhibit all RAF isoforms without causing paradoxical activation. Combination therapies, such as combining RAF inhibitors with MEK inhibitors or other pathway inhibitors, are also being explored to achieve more comprehensive pathway blockade and overcome drug resistance.