Ancient RAB35 Protein’s Role As A Cancer Cause (Cancer Study)

A new cancer study shows a protein responsible for the transportation of molecular contents inside and outside of the various intracellular compartments in the normal cells can also lead to the formation of cancer by activating a major growth-control pathway.

Mutated RAB35 and cancer

Researchers at the Institute of Whitehead and Memorial Sloan-Kettering Cancer Center have conducted a large-scale research on the signaling pathway regulators such as PI3K/AKT that promotes the cell growth, survival and proliferation with maximum activity in cancer cells and have related the protein RAB35 to the process of cancer formation. The study findings got published in an online journal “Science.”

Douglas Wheeler, the first author of the paper and also a former science student in lab of David Sabatini, a Whitehead member, says that, the majority of tumors turn on this pathway on their own, but in a large number of tumors and cell lines the cause of PI3K/AKT activation is not always the mutation.

Here the question arises whether there are any new regulators of this pathway. The answer to this is that the wild-type RAB35 is important in the PI3K/AKT pathway signaling. The mutant form of RAB35 stimulates the signaling of P13/AKT that can cause cell transformation from normal to cancerous, according to Wheeler.

Wheeler and his team have targeted RAB35 via RNA interference (RNAi) screen for genes regulating the pathway. Besides the identification of multiple known regulators of the pathway, the screen has also directed several genes that are not found previously. These regulators were then compared against a database of genes with mutations seen in human cancers. The results were narrowed down from a total of  7,500 to only 26 regulators of interest.

Wheeler admits that although the mutations in RAB35 present in human cancers are rare,  When present in tumors, they appear as true driver mutations. He further highlighted that the exact mechanism of oncogenesis in these mutations, that is the activation of a key signaling pathway by an alteration in the movement of some growth factor receptors is interesting.

Wheeler, now a postdoctoral fellow at Broad Institute and the Dana-Farber Cancer Institute states that,this  an attractive mechanism.

In this mechanism, RAB35 causes internalization of the receptor and activates the pathway. This cancer study shows the important role of dysregulated membrane trafficking in the process of cancer formation, he added.
Source: New role for an old protein: cancer causer, September 3, 2015