Inhibitor protein makes viable drug target
fundamental inhibitor of cell movement or migration, may be a
likely target for new drug development aimed at decreasing tumour
metastasis, or spread, throughout the body.
Increased tumour cell migration is one of the hallmarks of aggressive, rapidly spreading cancer tumours and such a discovery could well form a basis of a targeted therapy. Inhibiting the cell migration process that allows the process of tumour blood vessel formation could well become a direction that opens up new possibilities.
The protein, CIB1, or calcium and integrin-binding protein 1, was originally discovered as a blood platelet protein that may play a role in clotting. Subsequently, this latest study indicates that CIB1 inhibits cell migration by binding to and activating a protein called PAK1, or p21-activated kinase, in cancer cells.
The researchers, from the University of North Carolina, said that cells with less CIB1 had less PAK1 activation and migrated faster. The authors also showed that the more CIB1 these cells had, the less likely they were to move.
"CIB1 plays a prominent role in the activation of PAK1 and potentially may be another important player in the regulation of this kinase," said Tina Leisner, associate professor of pharmacology at UNC and the study's lead author.
The other activators of PAK1 include relatives of the Ras family of tumour promoters, the GTPases Rac and Cdc42. CIB1 activation of PAK1, however, is different from these GTPases.
"CIB1 activates PAK1 before Rac and Cdc42," said Leslie Parise, UNC professor of pharmacology.
"The time course of PAK1 activation never synched up with the time course of Rac and Cdc42 activation; now we know why - it was probably CIB1 that was activating PAK1 and not the Ras relatives," she added.
The key to understanding CIB1's multifunctional role in humans is that the protein has a relative, calmodulin that behaves in a very similar multifunctional fashion.
CIB1 is very similar to the protein calmodulin, which binds to a host of other proteins and regulates numerous cell functions, the fact that CIB1 and calmodulin are so similar could suggest that CIB1 may play multiple roles in multiple cell types.
Calmodulin is a calcium-binding protein that can bind to and regulate a multitude of different protein targets, thereby affecting many different cellular functions. It mediates processes such as inflammation, metabolism, apoptosis, muscle contraction, intracellular movement, short-term and long-term memory, nerve growth and the immune response.
"Our study of CIB1 is still very much in its early days, but its role in migration is already very clear," Parise said.
The study appears in the August issue of The Journal of Cell Biology.
