Education and Training
Bachelor of Arts in Biology, Carleton College, Northfield, MN, 1988
Ph.D. in Genetics, University of Washington, Seattle, 1996
Postdoctoral Fellow, Department of Genetics, University of Washington, Seattle, 1996-1997
Damon Runyon Cancer Research Foundation Postdoctoral Fellow, Division of Genetics and Development, University of California, Berkeley, 1997-2000
Howard Hughes Medical Institute Postdoctoral Fellow, Division of Genetics and Development, University of California, Berkeley, 2000-2002
Co-corresponding author and designer of cover layout for January 23, 2014 issue of Molecular Cell:
The Reiner lab research is divided into two general areas: mechanisms of cell signaling and harnessing model genetic organisms for drug discovery and translational biology.
Many oncogenes and tumor suppressor genes regulate signaling cascades that determine cell fate, proliferation, invasion, metastasis and other aspects of tumorigenesis. Traditionally such cascades are known as “pathways,” in large part due to a) the legacy of mostly linear (or so we thought at the time) biosynthetic pathways, and b) the essential nature of many core cascade components in evolutionarily diverse experimental organisms. However, diverse lines of reasoning argue that parallel signaling “pathways” are actually linked together as signaling networks to either work in concert or opposition to evoke a novel outcome. Furthermore, network plasticity is dynamically and spatiotemporally regulated during development, and probably tumorigenesis, to utilize divergent cascade effectors or partners to enact wildly dissimilar biological outcomes. We hypothesize that the notorious heterogeneity between and within cancer types with similar mutational profiles, both in cascade activation and pharmacological response, is a reflection of different tumor evolutionary clades utilizing diverse signaling partners.
We seek to identify novel network nodal points and dissect the mechanisms by which dynamic signal changes are regulated. Our system is the developing vulva of the nematode worm C. elegans, a classic genetic model organism. Most mammalian tumors arise from epithelial cells that are responding to extracellular growth factor signals. The vulva, a specialized epithelial tube, is similarly derived from an epithelial group responding to Epidermal Growth Factor (EGF) and the EGF receptor, and further patterned by Notch signaling. Each of six vulval precursor cells assumes the correct developmental fate with high fidelity. We found that the C. elegans ortholog of the small GTPase Ras, the most mutated oncoprotein in humans, dynamically switches signaling partners during vulval development, from the canonical Raf kinase to the RalGEF guanine nucleotide exchange factor that promotes Ral small GTPase signaling. Furthermore, these two effectors promote opposite and competing cell fates. Both Ras effectors are of critical importance in various human cancers. Our work provided the molecular mechanism to reconcile a long-standing conflict in the field, which was a proposed dual signaling of EGF to promote competing cell fates. We have extended this project to 1) show that RalGEF orchestrates two antagonistic cascades, Ral and PI3 Kinase, to fine-tune vulval developmental patterning, and 2) to characterize a Ral signaling cascade, a component of which may also orchestrate opposing signaling activities. Thus, a major theme of our research is signaling duality, a counterintuitive process by which the same protein can promote antagonistic outcomes. Our data suggest that signaling duality is a mechanistic underpinning of the emergent network property of exceptional developmental fidelity. Traditionally we think of DNA damage repair or cell cycle checkpoints as processes that impose informational or developmental fidelity, but we propose that signaling duality similarly enforces fidelity, perhaps in a way that prevents ambiguous cell fates that could subsequently lead to cancer.
A recent extension of this research, and a major new research focus, is our novel finding that Ral activates the central regulator of biosynthesis, metabolism, lifespan, diabetes, cancer, neurodegeneration, etc., TOR (Target of Rapamycin). We are excited to extend this finding into mechanistic analysis of TOR signaling.
The other general focus of the Reiner lab is to harness the power of C. elegans genetics to engineer animals for highly sensitized drug discovery screens. Here in the IBT Center for Translational Cancer Research on the 9th floor of the Alkek building is the John S. Dunn High Throughput Screening Core Facility, part of the Gulf Coast Consortia for Quantitative Biomedical Sciences. With them we are working to define a novel cross-platform drug discovery pipeline, with model organism small molecule inhibitor identification generating candidates for cell culture and mouse validation, and from there into the clinic. Consequently, our efforts are inherently collaborative. A key element of our project design is that, unlike conventional targeted drug therapy paradigms, we do not assume that we know the best target in a given system. Rather, we sensitize a system with a known mutation as an entry point for high throughput small molecule screening for specific phenotypic endpoints. We reason that the target identification can come later; we are looking for potentially valuable inhibitors in a given system regardless of the target, thereby complementing existing drug discovery paradigms. We began with oncogenic Rac and Ras as proofs of principle, and will extend to other entry points. We emphasize that in the long term our drug discovery scheme is generalizable: to other diseases with highly conserved molecular entry points (channelopathies, neurodegeneration, dystrophies, etc., as well as oncogenes) and to other model system platforms (yeast, worms, flies, frogs and fish).
Martin, TD, Chen, X-W, Kaplan, REW, Saltiel, AR, Walker, CL, Reiner, DJ§,†, Der, CJ. (2014). Ral and Rheb GTPase Activating Proteins Integrate mTOR and GTPase Signaling in Aging, Autophagy, and Tumor Cell Invasion. Molecular Cell 53: 209-220. PMID: 24389102
Dickinson, DJ, Ward, JD, Reiner DJ and Goldstein, B (2013). Engineering the C. elegans genome using Cas9-triggered homologous recombination. Nature Methods 1028-34. PMID: 23995389
Peters, EC, Gossett, AJ, Goldstein, B, Der, CJ, Reiner, DJ (2013). Redundant Canonical and Non-canonical C. elegans p21-Activated Kinase Signaling Governs Cell Migrations. G3 (Bethesda) 3: 181-195. PMID: 23390595
Reiner, DJ (2011) Ras Effector Switching as a Developmental Strategy. Small GTPases 2: 109-112. PMID: 21776412
Zand TP, Reiner DJ§,†, Der CJ (2011). Ras Effector Switching Promotes Divergent Cell Fates in C. elegans Vulval Patterning. Developmental Cell. 20: 84-96. PMID: 21238927
†Received two Faculty of 1000 citations
Neel, NF, Martin, TD, Stratford, JK, Zand, TP, Reiner, DJ, Der, CJ (2011). The RalGEF-Ral Effector Signaling Network: the Road Less Traveled for Anti-Ras Drug Discovery. Genes and Cancer. 2: 275-287. PMID: 21779498
Gonzalez-Perez, V, Reiner, DJ, Alan, JK, Mitchell, C, Edwards, LJ, Khazak, V, Der, CJ, Cox, AD. (2010) Genetic and functional characterization of putative Ras/Raf interaction inhibitors in C. elegans and mammalian cells. Journal of Molecular Signaling. 5: 2. PMID: 20178605
Reiner, DJ, Gonzalez-Perez, V, Der, CJ and Cox, AD (2008). Use of C. elegans to evaluate inhibitors of Ras function in vivo. Methods in Enzymology. 439: 425-449. PMID: 18374181
Reiner, DJ, Ailion, M, Thomas, JH, Meyer, BJ (2008) C. elegans anaplastic lymphoma kinase SCD-2 controls dauer formation by modulating TGF-beta signaling. Current Biology§. 18: 1101-9. PMID: 18674914
§Full length article
Reiner, DJ, Weinshenker, D, Tian, H, Thomas, JH, Nishiwaki, K, Miwa, J, Gruninger, T, Leboeuf, B, Garcia, LR (2006). Behavioral genetics of Caenorhabditis elegans unc-103-encoded erg-like K+ channel. Journal of Neurogenetics. 20: 41-66. PMID: 16807195
Petersen, CI, McFarland, TR, Stepanovic, SZ, Yang, P, Reiner, DJ, Hayashi, K, George, AL, Roden, DM, Thomas, JH, Balser, J.R. (2004). In vivo identification of genes that modify ether-a-go-go-related gene activity in Caenorhabditis elegans may also affect human cardiac arrhythmia. PNAS 101(32):11773-8. PMID: 15280551
Reiner, DJ, Newton, EM, Tian, H, Thomas, JH (1999). Diverse behavioral defects caused by mutations in Caenorhabditis elegans unc-43 CaM kinase II. Nature 402: 199-203. PMID: 10647014