Kenneth Yamada, M.D., Ph.D.
NIH Distinguished Investigator
Laboratory of Cell and Developmental Biology
Building 30, Room 426
30 Convent Drive
Bethesda, MD 20892
Our overall research goals are to discover novel mechanisms and regulators of cell interactions with the extracellular matrix and their roles in craniofacial development and disease pathogenesis. We are focusing on mechanisms by which the extracellular matrix, integrins, Rho family GTPase signaling systems, and the cytoskeleton act in concert to mediate or regulate cell adhesion, migration, invasion, matrix remodeling, and tissue morphogenesis. Recent projects have been exploring:
- how cell migration and invasion are mediated and regulated by integrated responses to three-dimensional (3D) extracellular matrix and ligand topography via integrins, signaling to the cytoskeleton, and focal proteolysis;
- how molecular cross-talk between adhesion, actomyosin, and microtubule systems coordinately regulates cell adhesion and migration;
- and the mechanisms by which key extracellular matrix molecules can activate stage-specific regulatory mechanisms in tissue morphogenesis involving high levels of cell migratory dynamics. We use various combinations of 1D, 2D, and 3D systems to explore these questions and to identify their molecular mechanisms.
Understanding these mechanisms of cell-matrix interactions and tissue morphogenesis should facilitate creative approaches to therapy, particularly in the fields of tissue engineering and cancer biology.
Our general approach has been to develop new methods to visualize and manipulate dynamics of specific molecules, cells, and tissues during cell migration and tissue morphogenesis. For example, over the past few years, we have developed novel approaches to (a) test roles of topography in migration, (b) visualize proteolysis by migrating cells at subcellular resolution, (c) document microanatomical changes in salivary gland gene expression, and (d) simultaneously visualize 3D cell movements and matrix dynamics during migration and tissue morphogenesis. These approaches have provided the following recent insights:
- Cell-matrix adhesions in 2D tissue culture have similar but not identical counterparts in 1D and various 3D matrix environments.
- Cellular functions are very similar in cells using 1D or 3D fibrillar matrix substrates, but they differ in 2D cell culture, e.g., with respect to mode of migration, roles of matrix concentration, stability of cell-matrix adhesions, requirements for polarized signal transduction, and dependence on myosin contractility.
- Cell migration and signal transduction can differ markedly in different 3D matrices.
- Tumor cell migration in 3D matrix involves focal proteolysis at the leading edge, especially in invadopodia, which are exceptionally dynamic compared to podosomes and focal adhesions.
- Extracellular matrix proteins can play key roles in tissue morphogenesis. For example, the matrix protein fibronectin can induce the novel regulator Btbd7, which in turn induces Snail2, down-regulates E-cadherin, and promotes cell scattering and cleft progression in salivary branching morphogenesis.
Our ongoing and future studies are focusing on extending these insights to (a) determine the mechanistic basis of rapid cell migration on 1D and 3D fibrils, (b) characterize distinct modes of cell migration in 3D and their regulation by Rho family GTPases, (c) delineate homeostatic mechanisms involving microtubules and contractility governing cell migration and morphogenesis, (d) define mechanisms and specific roles of local, controlled proteolytic degradation of fibrillar collagen or basement membranes in tissue and tumor expansion, and (e) determine how regulatory gene expression, local cell movements, and basement membrane remodeling are integrated to mediate tissue morphogenesis.
Throughout all of this research, we emphasize the training and career development of graduate students and postdoctoral fellows to become independent leaders in the field. We encourage them to take their projects with them if they wish in order to help start their own independent research careers.
Kenneth Yamada received B.A., M.D., and Ph.D. degrees from Stanford University. After serving as a section chief in the National Cancer Institute for 10 years, he has been a laboratory or branch chief at the NIDCR since 1990. He was elected a Fellow of the American Association for the Advancement of Science in 1991. He received the first Senior Investigator Award of the American Society for Matrix Biology in 2004, and in 2008 he received the Distinguished Scientist Award of the American Association for Dental Research. He was promoted to NIH Distinguished Investigator in 2011. Dr. Yamada has served on the Councils of the American Society for Cell Biology, International Society for Matrix Biology, American Society for Matrix Biology, and NIH Assembly of Scientists. He is an editor of The Journal of Cell Biology and serves as an associate editor or board member of a number of other journals including Matrix Biology, Journal of Cellular Physiology, Journal of Cell Science, Current Protocols in Cell Biology, and Journal of Dental Research. He has published more than 400 papers and reviews and is currently an Institute for Scientific Information 'Highly Cited Researcher'. He has given the Stadler and Swerling lectures at Harvard and M.D. Anderson Cancer Center, the Retzius Lecture at the Karolinska Institute, the Leonardo Lecture at the San Raffaele Research Institute, as well as a number of keynote and symposium lectures. He served a full term on the NIH Cell Biology Study Section and currently serves on the NIH Committee on Scientific Conduct and Ethics, Trans-NIH Mentoring Committee, and Senior Biomedical Research Service Policy Board.
Petrie RJ, Koo H, Yamada KM. Generation of compartmentalized pressure by a nuclear piston governs cell motility in a 3D matrix. Science. 2014;345(6200):1062-5.
Onodera T, Sakai T, Hsu JC, Matsumoto K, Chiorini JA, Yamada KM. Btbd7 regulates epithelial cell dynamics and branching morphogenesis. Science. 2010;329(5991):562-5.
Sakai T, Larsen M, Yamada KM. Fibronectin requirement in branching morphogenesis. Nature. 2003;423(6942):876-81.
Cukierman E, Pankov R, Stevens DR, Yamada KM. Taking cell-matrix adhesions to the third dimension. Science. 2001;294(5547):1708-12.
Miyamoto S, Teramoto H, Coso OA, Gutkind JS, Burbelo PD, Akiyama SK, Yamada KM. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J Cell Biol. 1995;131(3):791-805.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on September 11th, 2018