More than half of human cancers have abnormally upregulated chemical signals related to lipid metabolism, yet how these signals are controlled during tumor formation is not fully understood.

Youhai Chen, PhD, MD, and Svetlana Fayngerts, PhD, both researchers in the department of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania, and colleagues report that TIPE3, a newly described oncogenic protein, promotes cancer by targeting these pathways.

Lipid second messengers play cardinal roles in relaying and amplifying signals from outside the cell to its interior and outer membrane. One of the best known lipid second messengers is PIP3, which relays signals from hundreds of membrane receptors, including many oncogenic receptors, on the cell surface to PIP3-binding proteins in the cell’s interior, which control cell growth, differentiation, migration, transformation, and death.

Therefore, drugs targeting PIP3 – when its function goes awry -- may be effective for treating a variety of diseases, including cancer and inflammatory disorders. TIPE3 belongs to a newly described family of proteins and is a risk factor for human cancer and inflammation, although its mechanisms of action are largely unknown.

Chen and colleagues discovered that TIPE3 is the transfer protein of the second messenger PIP3 and it is hijacked by cancer cells to cause runaway cell division.

The high-resolution crystal structure of TIPE3 shows a large cavity that captures and transfers PIP3 and its chemical precursor PIP2 to increase their presence on the inner membrane of the cell. This promotes activation of downstream PIP3 effectors that cause cancer.

Click here to view the full release.