Environmental Factor, July 2008, National Institute of Environmental Health Sciences
Cell Migration and Metastatic Cancer Cell Behavior
By Dixie-Ann Sawin
On July 11, visiting lecturer Leslie Rivera Rosado summarized her research data on cell migration mechanisms for an audience of NIEHS scientists. Her seminar, "Role of ?4?1-Integrin in Cell Migration," was hosted by Steven Akiyama, Ph.D., lead investigator of the Cell Adhesion group within the Laboratory of Molecular Carcinogenesis.
Rivera is a seventh-year biochemistry, cellular and molecular biology graduate student in the lab of Joy Yang, Ph.D., at Johns Hopkins University in Baltimore, Maryland. The primary aim of her work in the Yang lab (http://www.hopkinsmedicine.org/cellbio/profiles/profdisplay.cfm?senduserID=16&sendpage=directory) is to elucidate regulatory mechanisms involved in cell migration with the hope of increasing the understanding of roles played by integrin-mediated molecular interactions in cancer.
Rivera's talk focused on alpha4beta1 (?4?1)-integrin, a unique member of the integrin superfamily that is involved in regulating directional cell migration. This integrin belongs to a subgroup that not only mediates extracellular matrix adhesion, but can also play roles in cell-cell adhesion in placental and cardiac development as well as tumor angiogenesis. As Rivera explained, her interest in this field stems from the relevance of such migratory mechanisms to metastatic tumor cell progression.
Rivera presented results of her recently published work (http://www.ncbi.nlm.nih.gov/pubmed/18495811?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) , for which she was a co-first author. In the study, she used the Shear Flow Assay to examine the role of ?4?1-integrin in cell migration in Chinese Hamster Ovary (CHO) cells. Fluid shear stress is associated with changes in blood flow which can impact angiogenesis and tumor development. Using this model, she questioned whether molecular interactions between ?4?1-integrin and paxillin, the signaling adaptor protein, influenced cell migration.
In her study, she ectopically expressed wild type and mutant forms of ?4?1-integrin in CHO cells and observed that ?4?1-integrin promotes directional cell motility - a mechanism that involves formation of membrane protrusions, known as lamellipodia, at the leading edge of cells and retraction at the trailing edges. In her presentation, Rosado showed short videos that clearly demonstrated migratory differences between wild type and mutant CHO cells.
The model underscored the importance of molecular interactions between the only known phosphorylation site (Ser988) on the ?4 integrin subunit and the paxillin-binding site (Y991A) in mediating cell polarity and migration of cells. Rivera showed that disrupting both phosphorylation and paxillin sites led to unstable cell polarization and that these interactions may have an effect on Rac and Rho GTPase-mediated pathways. She also determined that ?4?1-integrin can associate with the non-muscle myosin heavy chain IIA protein and that this association also plays an important role in regulating cell migration. Her work provides novel insight into the role played by integrins in cell migration and metastatic tumor cell growth.
(Dixie-Ann Sawin, Ph.D., is a post-doctoral research fellow in the Laboratory of Neurobiology/Neurotoxicology Group.)