CLIC4 Moves Into Nucleus to Stabilize Anti-Growth Signal

Art shows that in a normal cell, a protein called CLIC 4 responds to activation by a molecule called tgf-beta that signals on the cell surface for growth to slow down.  CLIC4 works through other proteins called smads to inhibit cell growth.  CLIC4 does not function properly in cancer cells, so growth inhibition does not occur.

Art shows that in a normal cell, a protein called CLIC 4 responds to activation by a molecule called tgf-beta that signals on the cell surface for growth to slow down. CLIC4 works through other proteins called smads to inhibit cell growth. CLIC4 does not function properly in cancer cells, so growth inhibition does not occur.

In cancer, the delicate balance of signaling pathways that control cell growth and function is disrupted. One signaling pathway commonly altered in cancer is the TGF-beta pathway. TGF-beta significantly inhibits growth of normal cells, particularly epithelial cells. Many cancer cells have developed ways to bypass one or more steps of this pathway in order to achieve uncontrolled growth. TGF-beta binds to receptors on the cell surface, which in turn activate (via phosphorylation) proteins inside the cell called Smad2 and Smad3. Activated Smad2 and 3 independently interact with another protein-Smad4-and then travel into the nucleus where they increase expression of proteins that inhibit the cell cycle and inhibit expression of proteins that drive cell division.

 

The activity of this seemingly simple relay team can be modified by numerous other proteins that affect the function of pathway members or their interaction with one another. For example, the ability of Smad2 and 3 to regulate gene expression can be subverted by nuclear proteins capable of removing the activating phosphate groups from the Smads.

A study recently published in Nature Cell Biology by Anjali Shukla, Ph.D., a postdoctoral fellow working with CCR Laboratory of Cancer Biology and Genetics researcher Stuart Yuspa, M.D., sheds light on additional proteins that influence TGF-beta signaling.

Shukla and colleagues were studying a growth inhibitory protein called CLIC4 whose function appears to be compromised in epithelial cancers. Using a genetically engineered gene that measures expression of TGF-beta regulated genes, the researchers determined that CLIC4 enhances TGF-beta-induced gene expression; this effect requires the presence of another protein called Schnurri-2. The link between TGF-beta signaling and CLIC4 was reinforced by experiments revealing that the growth inhibitory effects of CLIC4 are dependent on the presence of Smad3.

The researchers observed that treatment of cells with TGF-beta stimulates the interaction of CLIC4 and Schnurri-2 in the cytoplasm and promotes movement of this protein duo to the nucleus. Once in the nucleus CLIC4 separates from Schnurri-2 and interacts with activated Smads, preventing them from being dephosphorylated. CLIC4 protection of the Smads augments and prolongs the cell's response to TGF-beta, leading to enhanced inhibition of cell growth.

Increased knowledge of the TGF-beta pathway should lead to new strategies for modulating TGF-beta signaling in order to abrogate cancer growth and progression. The data from this study suggest that loss of CLIC4 function in cancer cells could help tumors resist the growth inhibitory signals of TGF-beta. Thus, restoration of CLIC4 function may provide some benefit for patients.

Summary Posted: 06/2009

Reference

Nat Cell Biol. 2009 May 17. [Epub ahead of print] PubMed Link