News and Publications

Chairman's Overview

Sandra Schmid, Ph.D.

Mergers are common events in the corporate world because they provide new opportunities for the synergistic development of ideas and technology, expand areas of expertise, diversify interests, and complement existing efforts to enhance overall effectiveness. For these same reasons, the incorporation of the Department of Vascular Biology as a division within the Department of Cell Biology this year qualifies as a scientific highlight. Members of the new division continue to study basic cell biological functions such as cell-cell and cell-matrix interactions, cell migration and metastasis, signal transduction, the production and modification of the extracellular matrix, and development. Thus, this merger will formalize and enhance beneficial interactions within our department. From the perspective of the Department of Cell Biology, this merger broadens the spectrum of our research toward probing complex cell physiology in the context of tissues and whole organisms. Moreover, vascular diseases are the leading cause of death and disability in the United States. Thus, understanding cell function in the context of the vascular system has important implications for human health. This merger strengthens our commitment to medically relevant and beneficial research.

We also undertook a spin-off of sorts and were pleased to open phase 1 of the Center for Integrative Molecular Biosciences on the expanding eastern campus of TSRI. Under the leadership of Ron Milligan, the long-term objective of the center is to unravel the intricate and integrated functions of complex, multicomponent cellular machines that mediate such essential processes as cell motility and division, signal transduction, transcription, and intracellular transport. These micromachines are obligatorily dynamic structures; thus, the center's goals will be accomplished through interdisciplinary research and the use of advanced technologies that facilitate determination of the structure and mechanism of action of the machines. Phase 1 emphasizes using state-of-the-art electron microscopy to determine the structures of macromolecules in the molecules' physiologic environments and in different dynamic states. Phase 2, which will begin in January 2003, will emphasize analysis of the dynamic behavior of these cellular machines in real time and space in the context of the living cell.

The laboratories of members of the Department of Cell Biology are scattered throughout the TSRI campus, with few sites of concentration. Thus, formal opportunities for intradepartmental interaction are critical. One opportunity is provided by the bimonthly breakfast meetings at which faculty members present their latest, most interesting findings and exchange ideas and suggestions. Guest speakers from other departments update us on new technologies and opportunities for collaboration.

An annual, full-day departmental retreat provides an opportunity for postdoctoral fellows, students, and research associates to present the results of their research to one another and to the faculty. This year 75 posters were presented and enthusiastically discussed. Nine fellows were selected, with much difficulty because of the overall excellence of the submissions, to present their work orally as "Departmental Highlights." I summarize their uniformly outstanding presentations here, giving much-deserved credit to the young researchers who spearheaded the work. Naturally, others not mentioned participated in these studies, and their contributions are acknowledged in the following pages of the annual report and in the publications describing these results.

Andrea Peier, a researcher in Ardem Patapoutian's laboratory, presented her discovery of a transient receptor potential (TRP) channel that senses cold stimuli. Like its distant relative the capsaicin receptor that senses heat and the spice from hot chili peppers, the cold-sensing TRP channel also responds to menthol, explaining the "cool refreshing" we experience when tasting mints. Researchers in Dr. Patapoutian's group continue to use molecular and bioinformatic approaches to identify other TRP channel family members and to determine the sensory functions of the channels.

Tom Schultz, a researcher in Steve Kay's laboratory, presented data on the discovery and characterization of transcription factors that regulate circadian function in plants. The concepts learned from the simple plant Arabidopsis apply equally to fruit flies and mammals. The researchers in Dr. Kay's group continue to make significant progress in unraveling the molecular mechanisms that govern circadian rhythms in humans.

Eleni Tzima, from the laboratory of Martin Schwartz, described integrin-mediated signaling cascades that involve the spatial reorganization and activation of Rho family GTPases that control the response of vascular endothelial cells to fluid shear stress. These responses, including the reorientation of endothelial cells in the direction of the flow, are important in vascular remodeling, in the regulation of blood pressure, and in the development of atherosclerosis.

Sean Conner, from my laboratory, presented his discovery of a new protein kinase that regulates receptor-mediated endocytosis at the level of selection and recruitment of receptors into clathrin-coated pits for uptake into the cell. Although the identity of coat proteins that mediate receptor recruitment and formation of endocytic vesicles has long been known, little was known about how their assembly and function are regulated.

Ongoing structural studies by researchers in Ronald Milligan's group continue to unravel the mechanistic diversity of molecular motors that is not apparent from the sequence differences of the motor proteins. Carolyn Moores presented elegant structural studies on a subclass of kinesin motors, Kin1, that rather than traveling along microtubules depolymerizes them. Her results revealed that instead of using the typical power stroke to move laterally along a microtubule template, the Kin1 motor domain binds to and bends the underlying filament, thus destabilizing the filament.

The nuclear import receptor importin b binds cargo molecules in the cytoplasm and through interactions with nucleoporin components of the nuclear pore, delivers the cargo into the cell nucleus. Earlier research in the laboratory of Larry Gerace indicated that the N-terminal half of importin b was sufficient for delivery of some, but not all, cargos to the nucleus. Janna Bednenko took a structural comparison approach to identify a putative second set of nucleoporin-binding sites on the C-terminal half of importin b , on the opposite side of the cargo-binding site. Molecular confirmation of the role of these residues in binding to nucleoporins and their requirement for efficient translocation through the nuclear pore complex supports the hypothesis that importin b evolved for optimum function through duplication of a single ancestral gene.

Tropomodulin was discovered by Velia Fowler in erythrocytes and muscle cells and plays a critical role in regulating the length of actin filaments in these cells (short and long, respectively) by capping the so-called pointed ends of actin filaments and controlling the rate-limiting step in the assembly of the filaments. Robert Fischer provided convincing evidence that a newly identified and ubiquitously expressed isoform, tropomodulin 3, is also critical in controlling actin dynamics in motile cells. Overexpression of tropomodulin 3 in migrating endothelial cells alters the kinetics of actin depolymerization and polymerization and inhibits cell motility. Thus, tropomodulin 3 may be an important cellular and/or therapeutic target for regulating cell migration in development or during angiogenesis.

Research by Clare Waterman-Storer revealed that cell migration requires the interplay between actin filaments and microtubules at the leading edge. A member of her group, Torsten Wittmann, provided mechanistic insight into the coordinated activity of these 2 cytoskeletal components. He showed that Pak1 kinase, which is activated by Rho family GTPases, long known to regulate actin dynamics, phosphorylates the protein Op18/stathmin, a regulator of microtubule depolymerization. The depolymerizing activity of Op18/stathmin is inhibited by Pak1-mediated phosphorylation, and as a consequence, microtubules at the leading edge are stabilized. Interfering with this signaling cascade in vivo inhibits cell migration.

Clearly, cell motility requires the intracellular coordination of actin and microtubule dynamics, but cells migrate along surfaces and in response to specific cues. These extracellular interactions and cues depend on surface integrins. Researchers in the laboratory of Mark Ginsberg showed that interactions between the cytoplasmic domains of integrins and the cytoskeleton function in transmitting both inside-out and outside-in signals; that is, cytoplasmic interactions can activate integrins and alter the binding affinities of the integrins for extracellular ligands, and conversely, ligation of integrins can transmit signals that alter the underlying actin cytoskeleton. David Calderwood identified 2 actin-binding proteins, talin and filamin, that bind to the cytoplasmic tail of b integrins to control bidirectional integrin signaling. In inside-out signaling, talin links integrins to the actin cytoskeleton and activates them. In outside-in signaling, filamin acts as a negative regulator of integrin-dependent cell migration.

I have highlighted the work of the more than 160 postdoctoral fellows in our laboratories. These fellows constitute the main body of our department and are our main strength. These talented and hard-working young scientists come to TSRI for a 3- or 4-year training period to fine-tune and hone their skills as independent investigators. Many are awarded prestigious and highly competitive fellowships to pursue their studies. They leave TSRI to contribute to outstanding applied research in biotech and pharmaceutical companies in San Diego and elsewhere or to pursue their own careers in academia as teachers, scholars, and basic researchers.