Xaralabos "Bob" Varelas, Assistant Professor, Boston University School of Medicine

Boston, MA

Current Site Of Practice: Boston University School of Medicine
Hospital Affiliation: Boston Medical Center
Focus of Research:
Fellowship Year: 2011 – 2012
Attended: University of Alberta

Contact Xaralabos "Bob" Varelas

Publications

Integrating developmental signals: a Hippo in the (path) way

Co-Authors Alain Mauviel, Flore Nallet-Staub

The Hippo pathway, a signaling cascade that controls cell cycle progression, apoptosis, and cell differentiation, has emerged as a fundamental regulator of many physiological and pathological processes. Recent studies have revealed a complex network of interactions directing Hippo pathway activity, and have connected this pathway with other key signaling pathways. Such crosstalk has uncovered novel roles for Hippo signaling, including regulation of TGF&live;/SMAD and WNT/&live;-catenin pathways. This review highlights some of the recent findings in the Hippo field with an emphasis on how the Hippo pathway is integrated with other pathways to mediate diverse processes. 

Oncogene. 2012 Apr 5;31(14):1743-56. doi: 10.1038/onc.2011.363. Epub 2011 Aug 29.

More: http://www.nature.com/onc/journal/v31/n14/full/onc2011363a.html

Coordinating developmental signaling: novel roles for the Hippo pathway

Co-Authors Jeffrey L. Wrana

Genetic and biochemical studies have defined the Hippo pathway as a central mediator of developmental and pathogenic signals. By directing intracellular signaling events the Hippo pathway fine-tunes cell proliferation, cell death, and cell fate decisions, and coordinates these cues to specify animal organ size. Recent studies have revealed that Hippo pathway-mediated processes are interconnected with those of other key signaling cascades, such as those mediated by TGF&live; and Wnt growth factors. Moreover, several reports have described a role for cell contact-mediated polarity proteins in Hippo pathway regulation. Emerging details suggest that crosstalk among these signals drive fundamental developmental processes, and deregulated intercellular communication influences disease progression, such as cancer. Here, we review recent data with a focus on how the Hippo pathway integrates its activity with other signaling pathways.

 

Trends Cell Biol. 2012 Feb;22(2):88-96. Epub 2011 Dec 5.

More: http://www.cell.com/trends/cell-biology/abstract/S0962-8924(11)00212-1

Integrating developmental signals: a Hippo in the (path)way.

Co-Authors Alain Mauviel, Flore Nallet-Staub

The Hippo pathway, a signaling cascade that controls cell cycle progression, apoptosis and cell differentiation, has emerged as a fundamental regulator of many physiological and pathological processes. Recent studies have revealed a complex network of interactions directing Hippo pathway activity, and have connected this pathway with other key signaling pathways. Such crosstalk has uncovered novel roles for Hippo signaling, including regulation of TGFlive/SMAD and WNT/live-catenin pathways. This review highlights some of the recent findings in the Hippo field with an emphasis on how the Hippo pathway is integrated with other pathways to mediate diverse processes.

Oncogene. 2011 Aug 29. doi: 10.1038/onc.2011.363. [Epub ahead of print]

More: http://www.ncbi.nlm.nih.gov/pubmed/21874053

TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal.

Co-Authors Rui Sakuma, Payman Samavarchi-Tehrani, Raheem Peerani, Balaji M. Rao, Joanna Dembowy, Michael B. Yaffe, Peter W. Zandstra and Jeffrey L. Wrana

Transforming growth factor-live (TGFlive) family members regulate many developmental and pathological events through Smad transcriptional modulators. How nuclear accumulation of Smad is coupled to the transcriptional machinery is poorly understood. Here we demonstrate that in response to TGFlive stimulation the transcriptional regulator TAZ binds heteromeric Smad2/3–4 complexes and is recruited to TGFlive response elements. In human embryonic stem cells TAZ is required to maintain self-renewal markers and loss of TAZ leads to inhibition of TGFlive signalling and differentiation into a neuroectoderm lineage. In the absence of TAZ, Smad2/3–4 complexes fail to accumulate in the nucleus and activate transcription. Furthermore, TAZ, which itself engages in shuttling, dominantly controls Smad nucleocytoplasmic localization and can be retained in the nucleus by transcriptional co-factors such as ARC105, a component of the Mediator complex. TAZ thus defines a hierarchical system regulating Smad nuclear accumulation and coupling to the transcriptional machinery.

Nat Cell Biol. 2008 Jul;10(7):837-48

More: http://www.nature.com/ncb/journal/v10/n7/full/ncb1748.html

The Hippo Pathway Regulates Wnt/live-Catenin Signaling

Co-Authors Bryan W. Miller, Richelle Sopko, Siyuan Song, Alex Gregorieff, Frederic A. Fellouse, Rui Sakuma, Tony Pawson, Walter Hunziker, Helen McNeill, Jeffrey L. Wrana, Liliana Attisano

Several developmental pathways contribute to processes that regulate tissue growth and organ size. The Hippo pathway has emerged as one such critical regulator. However, how Hippo signaling is integrated with other pathways to coordinate these processes remains unclear. Here, we show that the Hippo pathway restricts Wnt/live-Catenin signaling by promoting an interaction between TAZ and DVL in the cytoplasm. TAZ inhibits the CK1delta/epsilon-mediated phosphorylation of DVL, thereby inhibiting Wnt/live-Catenin signaling. Abrogation of TAZ levels or Hippo signaling enhances Wnt3A-stimulated DVL phosphorylation, nuclear live-Catenin, and Wnt target gene expression. Mice lacking Taz develop polycystic kidneys with enhanced cytoplasmic and nuclear live-Catenin. Moreover, in Drosophila, Hippo signaling modulates Wg target gene expression. These results uncover a cytoplasmic function of TAZ in regulating Wnt signaling and highlight the role of the Hippo pathway in coordinating morphogenetic signaling with growth control.

Dev Cell. 2010 Apr 20;18(4):579-91

More: http://www.cell.com/developmental-cell/abstract/S1534-5807(10)00113-9

The Crumbs Complex Couples Cell Density Sensing to Hippo-Dependent Control of the TGFlive/Smad Pathway

Co-Authors Payman Samavarchi-Tehrani, Masahiro Narimatsu, Alexander Weiss, Katie Cockburn, Brett G. Larsen, Janet Rossant, Jeffrey L. Wrana

The Hippo pathway senses cell density information to control tissue growth by regulating the localization of the transcriptional regulators TAZ and YAP (TAZ/YAP). TAZ/YAP also regulate TGFlive/SMAD signaling, but whether this role is linked to cell density sensing is unknown. Here we demonstrate that TAZ/YAP dictate the localization of active SMAD complexes in response to cell density-mediated formation of polarity complexes. In high-density cell cultures, the Hippo pathway drives cytoplasmic localization of TAZ/YAP, which sequesters SMAD complexes, thereby suppressing TGFlive; signaling. We show that during mouse embryogenesis, this is reflected by differences in TAZ/YAP localization, which define regions of active SMAD2/3 complexes. Interfering with TAZ/YAP phosphorylation drives nuclear accumulation of TAZ/YAP and SMAD2/3. Furthermore, we demonstrate that the Crumbs polarity complex interacts with TAZ/YAP, which relays cell density information by promoting TAZ/YAP phosphorylation, cytoplasmic retention, and suppressed TGFlive signaling. Accordingly, disruption of the Crumbs complex enhances TGFlive; signaling and predisposes cells to TGFlive-mediated epithelial-to-mesenchymal transitions.

Dev Cell. 2010 Dec 14;19(6):831-44.

More: http://www.cell.com/developmental-cell/abstract/S1534-5807(10)00539-3