New role for an old protein: Cancer causer

September 3, 2015, Whitehead Institute for Biomedical Research

A protein known to play a role in transporting the molecular contents of normal cells into and out of various intracellular compartments can also turn such cells cancerous by stimulating a key growth-control pathway.

By conducting a large-scale search for regulators of the signaling pathway known as PI3K/AKT, which promotes cell survival, growth, and proliferation—and which is highly active in cancer cells—researchers at Whitehead Institute and Memorial Sloan-Kettering Cancer Center have implicated the protein RAB35 in the oncogenic process. Their findings are reported online this week in the journal Science.

"Most tumors find a way to turn this pathway on, but in many tumors and cell lines there aren't always mutations that would explain PI3K/AKT activation," says Douglas Wheeler, a former graduate student in the lab of Whitehead Member David Sabatini and first author of the Science paper. "Here we asked whether we could find new regulators of this pathway. What we found was that wild-type RAB35 is important in signaling for the PI3K/AKT pathway, and that mutant RAB35 activates PI3K/AKT signaling, which can transform cells from a normal to a cancerous state."

Wheeler and collaborators hit upon RAB35 via an RNA interference (RNAi) screen for genes that regulate the pathway (as measured by changes in AKT phosphorylation). While the screen identified multiple known pathway regulators, it also pointed to several genes not previously implicated. The researchers then compared these novel entrants against a database of genes with mutations found in human cancers. That sort narrowed the field from nearly 7,500 candidates at the outset to 26 regulators of interest.

An analysis of the reported cellular functions of the remaining suspects pointed to the family of so-called RAB proteins, known to regulate intracellular protein trafficking, leading the investigators to wonder whether aberrant trafficking could contribute to oncogenesis. Of this group of proteins, RAB35 emerged, in part because mutant forms have been found in human tumors. Through a series of experiments, the researchers cemented RAB35's role, establishing that elimination of the protein suppresses AKT phosphorylation (and, therefore, PI3K pathway activity), which suggested that RAB35 is necessary to activate PI3K/AKT signaling; and that cells expressing mutated forms of RAB35 found in human cancers can activate the PI3K/AKT pathway and turn cancerous in vitro.

Wheeler concedes that although reported mutations to RAB35 in human cancers are relatively rare, they seem likely to be true "driver" mutations when they are present in tumors. Further, he emphasizes that the precise way in which mutant RAB35 contributes to oncogenesis—activating a key signaling pathway by altering the movement of certain growth factor receptors through membranes into intracellular compartments—is particularly intriguing.

"The mechanism is compelling," says Wheeler, who is now a postdoctoral fellow at Broad Institute and the Dana-Farber Cancer Institute. "In this case, RAB35 internalizes the receptor and causes the pathway to be constitutively active. This suggests that there may be an important role in dysregulated membrane trafficking in oncogenesis."

Explore further: Hedgehog pathway key in tamoxifen-resistant breast CA

More information: Identification of an oncogenic RAB protein, Science, www.sciencemag.org/lookup/doi/ … 1126/science.aaa4903

Related Stories

Hedgehog pathway key in tamoxifen-resistant breast CA

November 6, 2012
(HealthDay)—Noncanonical Hedgehog (Hh) signaling is activated in tamoxifen-resistant tumors, and the phosphoinositide 3-kinase inhibitor/protein kinase B (PI3K/AKT) pathway plays a key role protecting Hh signaling molecules, ...

Researchers discover new mechanism in adrenal gland tumors

August 28, 2015
Scientists at the Helmholtz Zentrum München have elucidated a mechanism that is responsible for the development of adrenal gland tumors. They discovered that the BMP7 protein plays a key role in this process and that it ...

Researchers solve mystery of how AkT 'moves' from cytosol to cell membrane

July 30, 2015
Jialing Xiang, professor of biology at Illinois Institute of Technology, and her collaborators have solved a longtime mystery: how protein kinase (Akt), a key player in cell signaling, "moves" from the cytosol (fluid inside ...

New insights on control of pituitary hormone outside of brain has implications for breast cancer

October 1, 2012
The hormone prolactin is produced by the pituitary gland in the brain and then travels via the bloodstream to cells throughout the body, where it exerts multiple reproductive and metabolic effects, most notably on the breast ...

New drug combination therapy developed to treat leukemia

April 17, 2013
A new, pre-clinical study by researchers at Virginia Commonwealth University Massey Cancer Center suggests that a novel drug combination could lead to profound leukemia cell death by disrupting the function of two major pro-survival ...

Possible therapy for tamoxifen resistant breast cancer identified

August 30, 2012
(Medical Xpress)—A study by researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) has discovered how tamoxifen-resistant ...

Recommended for you

Daily low-dose aspirin may be weapon against ovarian cancer

July 20, 2018
(HealthDay)— One low-dose aspirin a day could help women avoid ovarian cancer or boost their survival should it develop, two new studies suggest.

Discovery of kidney cancer driver could lead to new treatment strategy

July 19, 2018
University of North Carolina Lineberger Comprehensive Cancer Center scientists have uncovered a potential therapeutic target for kidney cancers that have a common genetic change. Scientists have known this genetic change ...

High fruit and vegetable consumption may reduce risk of breast cancer, especially aggressive tumors

July 19, 2018
Women who eat a high amount of fruits and vegetables each day may have a lower risk of breast cancer, especially of aggressive tumors, than those who eat fewer fruits and vegetables, according to a new study led by researchers ...

Sunscreen reduces melanoma risk by 40 per cent in young people

July 19, 2018
A world-first study led by University of Sydney has found that Australians aged 18-40 years who were regular users of sunscreen in childhood reduced their risk of developing melanoma by 40 percent, compared to those who rarely ...

Analysis of prostate tumors reveals clues to cancer's aggressiveness

July 19, 2018
Using genetic sequencing, scientists have revealed the complete DNA makeup of more than 100 aggressive prostate tumors, pinpointing important genetic errors these deadly tumors have in common. The study lays the foundation ...

Complementary medicine for cancer can decrease survival

July 19, 2018
People who received complementary therapy for curable cancers were more likely to refuse at least one component of their conventional cancer treatment, and were more likely to die as a result, according to researchers from ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.