Menu

Cadherin Connection

A multitasking plasma membrane protein coordinates cell division and energy metabolism in healthy—and perhaps also cancerous—Drosophila cells.

Dec 1, 2014
Jyoti Madhusoodanan

ENERGY SWITCH: In quiescent fruitfly cells, a cell-adhesion molecule, Ft cadherin, inhibits growth by activating the Hippo pathway (above, left). Upon the severing of the cytosolic arm of Ft cadherin, the liberated piece enters a mitochondrion, where it interacts with two groups of proteins, Complex I and Complex V, promoting oxidative phosphorylation and lifting Hippo’s repression of growth (above, right). © KIMBERLY BATTISTA, BASED ON A. SING ET AL., CELL, 158:1293-1308, 2014.

EDITOR'S CHOICE IN CELL BIOLOGY

The paper
A. Sing et al., “The atypical cadherin Fat directly regulates mitochondrial function and metabolic state,” Cell, 158:1293-1308, 2014.

When clustered together in tissues, cells sense and respond to their neighbors by way of membrane receptors, which relay signals informing individual cells when and in what directions to multiply. The loss of—or failure to respond to—these cues can spill over to cause cancer or other diseases. Researchers previously knew that one such surface receptor, a conserved cell-adhesion molecule dubbed Fat (Ft) cadherin, functioned in two ways, regulating tissue organization and a tumor-suppressive signaling pathway known as Hippo. Now, a new study suggests this molecule may have a third role: linking cell proliferation to mitochondrial respiration.

In 2003, Helen McNeill of the University of Toronto and colleagues found that Ft cadherin—a giant protein with arms projecting from both sides of the cell membrane—binds to at least 58 different cytoplasmic proteins in fruit flies. So McNeill and her colleagues set out to find other roles Ft cadherin might play.

Using RNAi to reduce the expression of these binding partners one by one, the group examined the role of each protein in controlling growth and cell organization in Drosophila eye and wing cells. Surprisingly, they found the most disruptive effects when they knocked down a mitochondrial protein named Ndufv2, which is part of complex I, a group of respiratory enzymes embedded in the inner mitochondrial membrane. Deleting the section of Ft cadherin that binds this protein destabilized complex I, increased levels of reactive oxygen species (ROS), and incited cells to rely on aerobic glycolysis, rather than oxidative phosphorylation, for energy. Cells with a mutant version of the ft gene also showed significant structural defects in their mitochondria.

Further experiments revealed that Ft cadherin interacts with Ndufv2 by breaking off a chunk of its cytoplasmic arm, which enters the mitochondrion, where it modulates cellular respiration. “We were completely surprised to see this direct effect of Ft cadherin,” says McNeill. The results are “the first demonstration of direct regulation of mitochondrial complex stability by a cell surface protein,” the authors wrote in their paper. Still unknown are the triggers for cleaving Ft to produce the chunk that enters the mitochondrion.

Based on their data, the researchers propose that in quiescent cells, Ft acts at the exterior plasma membrane to suppress cell division and growth. But when the cleaved-off cytosolic Ft fragment enters the mitochondrion and binds to complex I, it powers up oxidative energy metabolism—while its detachment simultaneously lifts the cadherin’s inhibitory effect on proliferation. Thus this shift to the cleaved form that boosts energy and enables cell division is vital to ordered growth and development, but if dysregulated “may be foundational” to cancer cell growth, according to McNeill.

The results can help researchers “find better metabolic links” that explain how cancer cells continue to multiply even in crowded, hypoxic tissue environments, says Madhuri Kango-Singh of the University of Dayton in Ohio. “This is a molecular clue to understanding how cancer cells survive,” she says.

September 2018

The Muscle Issue

The dynamic tissue reveals its secrets

Marketplace

Sponsored Product Updates

Horizon Discovery introduces Myeloid DNA Reference Standard to support genetic testing of leukemia

Horizon Discovery introduces Myeloid DNA Reference Standard to support genetic testing of leukemia

Horizon Discovery Group plc, a global leader in gene editing and gene modulation technologies, today announced the launch of its Myeloid DNA Reference Standard. The first-to-market large cell-line derived myeloid cancer reference standard designed enables faster, more reliable and more cost-effective assay validation, to support the market in bringing routine testing into practice.

StemExpress LeukopakâNow Available in Frozen Format

StemExpress LeukopakâNow Available in Frozen Format

StemExpress, a Folsom, California based leading supplier of human biospecimens, announces the release of frozen Peripheral Blood Leukopaks. Leukopaks provide an enriched source of peripheral blood mononuclear cells (PBMCs) with low granulocyte and red blood cells that can be used in a variety of downstream cell-based applications.

New Antifade Mounting Media from Vector Laboratories Enhances Immunofluorescence Applications

New Antifade Mounting Media from Vector Laboratories Enhances Immunofluorescence Applications

Vector Laboratories, a leader in the development and manufacture of labeling and detection reagents for biomedical research, introduces VECTASHIELD® Vibrance™ – antifade mounting media that delivers significant improvements to the immunofluorescence workflow.

Best Practices for Sample Preparation and Lipid Extraction from Various Samples

Best Practices for Sample Preparation and Lipid Extraction from Various Samples

Download this white paper from Bertin Technologies to learn how to extract and analyze lipid samples from various models!