Scott Atwood, PhD

I will be giving a plenary talk and presenting a poster on aPKC function in drug-resistant basal cell carcinoma on May 10 at the International Investigative Dermatology (IID) meeting in Edinburgh, Scotland. I have also been awarded the IID Trainee Retreat Travel Fellowship. The IID meeting brings together the ESDR, SID, and JSID every five years to showcase exciting science, collegiality, and social interactions. Internationally renowned scientists will join the meeting and guarantee a stimulating exchange of the latest scientific information. Edinburgh was selected as the meeting venue for the IID meeting in 2013, because the city is well-connected to international travel and offers a multitude of congress facilities, accomodation, as well as a stimulating atmosphere. Edinburgh itself is a beautiful ancient city that reflects a lot of Old Europe in a charming way. Besides being a World Heritage City, Edinburgh also offers a special Scottish touch that is appreciated by many tourists every year and that makes the city one of the prime destinations for travellers in Britain. Read more.

Dependence of basal cell carcinomas and medulloblastomas on the Hedgehog pathway provides an opportunity for targeted or personalized therapy. The recent effectiveness and FDA approval of the first Smoothened inhibitors validates this class of agents, but has revealed drug-resistant tumor variants that bypass Smoothened inhibition. Here, we summarize the effectiveness of Hedgehog pathway inhibitors and highlight promising areas for the development of next generation drug antagonists for Hedgehog-dependent cancers. Read more.

I will be giving a talk and presenting a poster on how aPKC activates Hedgehog signaling during basal cell carcinoma growth at the American Society for Cell Biology Annual Meeting, located in San Francisco, from December 15-19. As the premier international meeting in the field of cell biology, the ASCB Annual Meeting is intended for scientists and students in academia, industry, government, and higher education. Over 100 scientific sessions and 3,000 poster presentations cover a variety of scientific areas within the discipline. With opportunities to learn about the latest research and network with peers, the ASCB Annual Meeting appeals to the diverse interests of the international cell biology community. Read more.

The meeting report for the Hedgehog Signalling in Development, Evolution, and Disease conference from EMBO reports is here and our work on aPKC-dependent regulation of Hedgehog signaling in basal cell carcinoma was highlighted in the Signalling section! The conference took place in Biopolis, Singapore and brought Hedgehog signaling experts together to discuss their latest work and exchange ideas. A striking mix of cultures combined with gleaming skycrapers and colonial buildings cultivated a brilliant meeting. Read more.

Atypical Protein Kinase C (aPKC) controls cell polarity by modulating substrate cortical localization. Aberrant aPKC activity disrupts polarity yet the mechanisms that control aPKC remain poorly understood. We used a reconstituted system with purified components and a cultured cell cortical displacement assay to investigate aPKC regulation. We find that aPKC is autoinhibited by two domains within its NH2-terminal regulatory half, a pseudosubstrate motif that occupies the kinase active site, and a C1 domain that assists in this process. The Par complex member Par-6, previously thought to inhibit aPKC, is a potent activator of aPKC in our assays. Par-6 and aPKC interact via PB1 domain heterodimerization and this interaction activates aPKC by displacing the pseudosubstrate, although full activity requires the Par-6 CRIB-PDZ domains. We propose that, along with its previously described roles in controlling aPKC localization, Par-6 allosterically activates aPKC to allow for high spatial and temporal control of substrate phosphorylation and polarization. Read more.

I will be giving a talk on how aPKC activates Hedgehog signaling during basal cell carcinoma growth at the Hedgehog Signalling in Development, Evolution, and Disease Conference held at Biopolis, located in Singapore, from March 18-21. The goal of the Hedgehog Conference is to bring together the leading researchers in the Hedgehog field to present their most recent findings and ideas. First discovered in Drosophila, Hedgehog signaling research over the past 15 years has revealed the essential role played by Hedgehog in development and disease. In fact, aberrant Hedgehog signaling is associated with 25% of all human cancers. The meeting reflects many areas of Hedgehog signaling, with sessions devoted to the mechanisms of signal transduction, developmental roles of Hedgehog, evolutionary origins of the pathway, involvement in human disease, and use as therapeutic targets. Dr. Wei-Meng Woo, a postdoctoral research fellow in the Oro lab, will also give a talk on a Noggin-Shh regulatory loop in the dermal papilla that regulates hair morphogenesis. Read more.

The meeting report for the Society for Investigative Dermatology is finally here and our work on aPKC regulation of basal cell carcinoma was highlighted in the Cancer section! An international group of about 1,500 researchers attended the SID meeting to hear cutting-edge research in skin health and disease. Almost 900 oral and poster presentations were given, and our work was one of the few highlighted in the meeting report. Fellow Stanford University postdoctoral scholars Markus Kretz and Carolyn Lee's work on long noncoding RNAs in skin differentiation and development was also highlighted. Congratulations! Read more.

I will be giving a talk and presenting a poster on aPKC-dependent regulation of basal cell carcinoma at the Epithelial Differentiation and Keratinization Gordon Conference held at Mount Snow Resort, located in West Dover, Vermont, during the first week in July. The goal of the Gordon Research Conference on Epithelial Differentiation and Keratinization is to provide a stimulating forum for the dissemination and discussion of new research, concepts and opportunities at the forefront of epidermal and epithelial biology. Since its inception in 1979, this conference has fostered interactions among clinical and basic scientists. The epidermis and its appendages have historically been a central focus, but the 2011 conference will include discussion of additional epithelial tissues and models. The aims of the Conference are to define the most important problems and opportunities at the frontiers of epithelial biology; further the development of young investigators; and introduce new concepts and advances from other fields. To accomplish these goals, the program for 2011 emphasizes exciting new research on the epidermal barrier; regulation and therapeutic applications of skin stem cells; the role of the immune system in epithelial biology and disease; signaling in epithelial homeostasis and cancer; and novel mechanisms involving regulatory RNAs, chromatin remodeling, and adhesion. Read more.

I will be giving a plenary talk and presenting a poster on novel factors that regulate Hedgehog signaling in basal cell carcinoma at the 2011 Society for Investigative Dermatology (SID) annual meeting in Phoenix. I have also been awarded the Albert M. Kligman Travel Fellowship. The SID was born out of a vision to serve a segment of science previously unrepresented by the medical societies of the United States: investigative dermatology. The founders saw a need for an organization with a devotion to cutaneous investigation, rather than clinical work, and to promote investigative dermatology to a fully respected position among the medical specialties. In tandem with the establishment of the society, they sought to develop a new scientific journal that would act as a singular resource for investigative work in cutaneous biology. Previously, this research had been scattered among the non-dermatology journals and had largely been completed outside the specialty of investigative dermatology. This vision was realized when the SID was founded, bylaws were adopted and a board of nine directors was appointed on June 10, 1937 at the Hotel Dennis in Atlantic City, New Jersey. The Journal of Investigative Dermatology (JID) was launched, with Marion B. Sulzberger as its first editor, and the first Annual Meeting was held in April 1938 in New York City. Read more.

Signaling circuits often coordinate cellular membranes and actin filaments at distinct sites to direct cell behavior. In this issue of Developmental Cell, Bershteyn et al. outline how the molecular scaffold protein, MIM, which bends membranes and binds actin filaments, is at the middle of one such circuit to regulate ciliogenesis. Read more.

The primary cilium is critical for transducing Sonic hedgehog (Shh) signaling, but the mechanisms of its transient assembly are poorly understood. Previously we showed that the actin regulatory protein Missing-in-Metastasis (MIM) regulates Shh signaling, but the nature of MIM's role was unknown. Here we show that MIM is required at the basal body of mesenchymal cells for cilia maintenance, Shh responsiveness, and de novo hair follicle formation. MIM knockdown results in increased Src kinase activity and subsequent hyperphosphorylation of the actin regulator Cortactin. Importantly, inhibition of Src or depletion of Cortactin compensates for the cilia defect in MIM knockdown cells, whereas overexpression of Src or phospho-mimetic Cortactin is sufficient to inhibit ciliogenesis. Our results suggest that MIM promotes ciliogenesis by antagonizing Src-dependent phosphorylation of Cortactin and describe a mechanism linking regulation of the actin cytoskeleton with ciliogenesis and Shh signaling during tissue regeneration. Read more.

Congratulations to all the authors on their hard work! Even though we didn't submit this particular image, the message is still appropriately conveyed. I'm glad they decided to use the arms of scientists!

Eugene, OR, USA. Biochemists from the University of Oregon (UO) have reported the discovery of an enzyme that acts as a traffic cop, directing which roads the daughter cells will take on their way toward specific component of the body. The team examined Drosophila miranda for a protein that is a crucial switch in determining the fate of a stem cell. Driving the Miranda gene is aPKC (Atypical Protein Kinase C Isoform), a member of a family of enzymes involved in controlling the function of other proteins. PKC enzymes play important roles in several consecutive signal conversions (signal transduction cascades). Defining the role of aPKC is important because it pinpoints the event that results in sorting out the futures of undifferentiated stem cells. Investigators can see more clearly how the duplication of a stem can result in a daughter cell such as a neuron that forms the central nervous system. Knowing the origin point of a neuron permits more detailed tracking of its subsequent development. Read more.

Driving Miranda, a protein in fruit flies crucial to switch a stem cell's fate, is not as complex as biologists thought, according to University of Oregon biochemists. They've found that one enzyme (aPKC) stands alone and acts as a traffic cop that directs which roads daughter cells will take. "Wherever aPKC is at on a cell's cortex or membrane, Miranda isn't," says Kenneth E. Prehoda, a professor in the chemistry department and member of the UO's Institute of Molecular Biology. When a stem cell duplicates into daughter cells, the side, or cortical domain, containing aPKC (atypical protein kinase C) continues as a stem cell, while the other domainwith Miranda becomes a differentiated cell such as a neuron that forms the central nervous system. Read more.

Asymmetric cell divisions generate daughter cells with distinct fates by polarizing fate determinants into separate cortical domains. Atypical protein kinase C (aPKC) is an evolutionarily conserved regulator of cell polarity. In Drosophila neuroblasts, apically restricted aPKC is required for segregation of neuronal differentiation factors such as Numb and Miranda to the basal cortical domain. Whereas Numb is polarized by direct aPKC phosphorylation, Miranda asymmetry is thought to occur via a complicated cascade of repressive interactions (aPKC inhibits Lgl, Lgl inhibits myosin II, myosin II inhibits Miranda). Here we provide biochemical, cellular, and genetic data showing that aPKC directly phosphorylates Miranda to exclude it from the cortex and that Lgl antagonizes this activity. Miranda is phosphorylated by aPKC at several sites in its cortical localization domain and phosphorylation is necessary and sufficient for cortical displacement, suggesting that the repressive-cascade model is incorrect. In investigating key results that led to this model, we found that Y-27632, a Rho kinase inhibitor used to implicate myosin II, efficiently inhibits aPKC. Lgl3A, a nonphosphorylatable Lgl variant used to implicate Lgl in this process, inhibits the formation of apical aPKC crescents in neuroblasts. Furthermore, Lgl directly inhibits aPKC kinase activity. Miranda polarization during neuroblast asymmetric cell division occurs by displacement from the apical cortex by direct aPKC phosphorylation. Rather than mediating Miranda cortical displacement, Lgl instead promotes aPKC asymmetry by regulating its activity. The role of myosin II in neuroblast polarization, if any, is unknown. Read more.