Surveying signalling pathways: the role of the RAS/MAPK pathway and its contribution to cancer

Posted by ap507 at Jun 30, 2016 04:18 PM |
PhD student Mohan Harihar outlines the importance of the RAS/MAPK pathway in cancer development
Surveying signalling pathways: the role of the RAS/MAPK pathway and its contribution to cancer

Epidermal growth factor receptor (EGFR) signaling pathway

Signalling pathways play a major role in both healthy and rogue cell biochemistry.

With different signalling pathways largely filling different niches inside the cell, it is possible to fulfil a range of functions and influence varying aspects of cellular behaviour. In doing so cells can continually adapt and progress with their “lives”. 

One important pathway in cellular biology is the ‘RAS/Mitogen-Activated Protein Kinase (MAPK) pathway’.

As with all signalling pathways, the RAS/MAPK pathway comprises a chain of proteins (in this case four proteins – RAS, RAF, MEK1/2 and MAPK) which need to be activated in sequence to bring about the desired response.

The primary function of this pathway is to promote cell ‘proliferation’ (or division), but through cross-interaction with other signalling pathways it is possible to control other aspects of cellular behaviour.

So how does the RAS/MAPK pathway work?

Generally speaking all pathways require some molecule (often a small protein) for activation. In the case of the RAS/MAPK pathway, the protein required for activation is known as a ‘mitogen’ – a small protein which has the ability to specifically trigger cell proliferation.

The mitogen will recognise and bind to a site on the outer surface of another protein (known as a ‘receptor’) which is embedded at the surface of the cell. This leads to a subtle modification in the receptor’s structure, notably the portion of the receptor which resides inside the cell. By achieving this, docking sites which can accommodate further proteins which serve to assist in the overall signalling ability of the pathway are created. This helps to build a larger ‘molecular scaffold’ of signalling molecules within the cell.

Activation of each of the proteins in sequence must then occur to effectively transmit the signal from the outer surface of the cell, where the mitogen originally bound to the receptor, to the inside of the cell. This is largely achieved through a process called ‘phosphorylation’, in which chemical additions known as ‘phosphate’ groups are tagged onto the majority of the core proteins making up the pathway. Through this process the tagged protein becomes biochemically

631pxHras_surface_colored_by_conservation.png
Structure of a version of RAS, H-RAS
active.

Proteins capable of phosphorylation are known as ‘kinases’ – in the case of the RAS/MAPK pathway, RAF, MEK1/2 and MAPK are all examples of such kinases.

As with all cellular mechanisms the activity of the pathway must be kept in check by regulators. These are in place to ensure the pathway does not remain active ‘constitutively’ (continuously) beyond completion of the required task.

The sequence of activation events

RAS is the first of the main signalling proteins in the RAS/MAPK pathway. Described as a ‘molecular switch’, RAS is responsible for ‘switching on’ and activating the protein next in line – RAF. In the case of RAS, it becomes activated (or ‘switched on’) when a small chemical molecule capable of energy release called ‘GTP’ is bound to it, and inactivated (‘switched off’) when the GTP molecule is broken down to ‘GDP’. The RAS-GTP complex proceeds to associate with and activate RAF.

RAF then proceeds to itself activate, via phosphorylation, two other proteins, MEK1 and MEK2.

The activated MEK proteins also have the capacity to phosphorylate other proteins. In this instance, the only target molecules for the MEK proteins is MAPK.

It is this chain-activation of proteins from RAS to MAPK that successfully conducts signals from receptors embedded at the cell surface to the DNA within the cell.

ERK2phosphorylated.png
Phosphorylated MAPK
By accomplishing this, MAPK can radically alter the amounts of growth-associated proteins by modifying the extent to which certain genes (present in the DNA) are expressed. This leads to processes such as cell cycle progression, differentiation, protein synthesis, metabolism, cell survival, cell migration and senescence (when a cell reaches its replicative limit and ceases to divide) being delicately controlled.

Nonetheless, activation of MAPK can lead to cells acquiring many of the ‘Hallmarks of Cancer’ due to the proliferative capacity of the pathway in question. Consequently, targeting this pathway has been seen as an attractive option to overcome the malignant phenotype.

Why is this pathway so important?

Disruption of the RAS/MAPK pathway is implicated in the onset of tumour development by causing cells to acquire the ‘Hallmarks of Cancer’. 

Defects in any one of the pathway proteins can theoretically alter its activity such that gratuitous cellular proliferation will ensue.

What is often observed in defective RAS/MAPK pathways is that the activity is massively increased – meaning the amount of cell proliferation which occurs is too high. This is often due to a mutation which prevents the GTP attached to RAS from being broken down.

It has also been shown that DNA defects (in the form of mutations) in the RAS protein can result in unwanted activation of the RAF protein. Crucially these mutations have been demonstrated to be the most common among ‘oncogenes’ (the term given to cancer-causing genes) – present in around 30% of all human cancers.

More detailed statistics reveal that the RAS/MAPK pathway is a major player in a number of cancers.

RAS mutations in particular can often be observed in these cancers - including approximately 90% of pancreatic cancers, 40% of colorectal cancers, 30% of non-small cell lung cancers, 30% of bladder cancers, 30% of peritoneal cancers (a cancer which originates in the thin tissue layers of the abdomen), 25% of cholangiocarcinomas (cancer of the bile duct) and 15% of melanomas.

Moreover approximately 3 million new cancers – including both solid tumours and blood-related cancers - are diagnosed each year across the globe in which RAS mutations are prevalent.

Another component of the RAS/MAPK pathway which, when mutated, is often implicated in cancer onset is the RAF protein (in particular a version of the protein referred to as B-RAF). B-RAF mutations are responsible for nearly 500,000 new cancers every year and are present in around 6% of all human cancers.

Given these facts it is clear why this pathway has attracted so much interest from scientists around the world.

Unexplored avenues

Expending time, effort and inevitably money on designing therapies for known components of the pathway is without doubt of paramount importance. Nevertheless, it is perhaps even more important for scientists to delve further into the depths of the unknown.

In doing this the number of prospective targets for therapy can grow by building upon the plethora of medication already in existence.

For example, in the laboratory of Dr Kayoko Tanaka, unpublished work suggests that there are potentially unknown regulators of the RAS/MAPK pathway – specifically a regulator which may be exerting its effect between RAS, the first component in the chain of proteins, and MAPK, the final component. It will be my aim to try and shed more light on this possibly undiscovered regulator.

If successful, the next step would involve analysing the structure of this protein regulator with the aim of identifying potential regions on it which could be targeted with newly designed specific drugs.

This is just one possibility with regards to unexplored avenues of research relating to the RAS/MAPK pathway.

 

From the points raised here it is clear that the RAS/MAPK pathway is an extremely attractive target for therapy and future research – largely due to the number of proteins involved. Furthermore by exploring more unknown aspects of such pathways we will hopefully be better placed in the future at tackling a range of different tumours.

 

Share this page: