- ADJUNCT ASSISTANT PROFESSOR Oncological Sciences
Laurea Degree, University of Genova
Immunogenetics Laboratory, IST, National Cancer Institute
Ruttenberg Cancer Center, The Mount Sinai Medical Center
ResearchWnt signaling plays a critical role in cell fate determination and tissue development and is highly conserved from C. Elegans to humans. Members of this family of secreted glycoproteins interact with two co-receptors, the Frizzled seven transmembrane receptor, and the low density receptor related protein LRP5/6. Wnt?"receptor interactions lead to inhibition of I2-catenin phosphorylation by the serine threonine kinase, glycogen synthase kinase-I2 (GSK-3I2) within a large cytoplasmic complex including Dishevelled (Dsh), APC and Axin. Inhibition of I2-catenin phosphorylation impairs its degradation by the ubiquitin/proteosome pathway. This results in accumulation of the uncomplexed cytosolic molecule which translocates to the nucleus and interacts with TCF/LEF to activate target genes. \r\n
Wnt signaling through its receptors is regulated by a number of naturally occurring secreted inhibitors including FRPs and DKKs. We have shown that FRPs act by binding and sequestering Wnt. Moreover, the ability of FRPs to form heterodimers with Fzs, which themselves form dimers, suggest the possibility that FRPs may also directly inhibit Fz signaling by a dominant negative mechanism. We have also characterized another Wnt inhibitor Dkk-1 and demonstrated that unlike all other Wnt inhibitor, DKK-1 specifically inhibits canonical signaling by binding the LRP6 component of the receptor complex. Wnts were initially identified as a consequence of their transcriptional activation by mammary tumor virus promoter insertion, which initiates tumor formation. Later studies established that constitutively activated Wnt signaling through alterations afflicting the intracellular mediators, APC, and I2-catenin, is crucially involved in several types of human cancer. We have identified human breast and ovarian carcinoma cell lines with Wnt pathway activation in the absence of mutations in APC/I2-catenin. The extracellular Wnt antagonists, FRP1 and DKK1 which block ligand/receptor interactions, caused a dramatic downregulation of Wnt signaling, establishing the presence of an autocrine mechanism in these tumor cells. Our research focuses on several aspects of Wnt signaling such as how Autocrine Wnt signaling influences the transformed phenotype of human tumor cells including their response to therapeutic agents and their stem/progenitor-like properties, the identification of the molecular mechanisms responsible for the establishment of Wnt autocrine signaling in these tumor cells, and the characterization of signaling through LRP6/frizzled receptors. An increasing number of cancer therapeutic agents are being directed against ligands or their cell surface receptors. Thus, autocrine Wnt signaling could provide a novel target for therapeutic intervention by means of Wnt antagonists or other modalities that interfere with cell surface interactions of Wnts and their receptors.
Bafico A, Gazit A, Wu-Morgan SS, Yaniv A, Aaronson SA. Characterization of Wnt-1 and Wnt-2 induced growth alterations and signaling pathways in NIH3T3 fibroblasts. Oncogene 1998 May 28; 16(21): 2819-2825.
Bafico A, Gazit A, Pramila T, Finch PW, Yaniv A, Aaronson SA. Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling. J Biol Chem 1999 Jun 4; 274(23): 16180-16187.
Fedi P, Bafico A, Nieto Soria A, Burgess WH, Miki T, Bottaro DP, Kraus MH, Aaronson SA. Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling. J Biol Chem 1999 Jul 2; 274(27): 19465-19472.
Gazit A, Yaniv A, Bafico A, Pramila T, Igarashi M, Kitajewski J, Aaronson SA. Human frizzled 1 interacts with transforming Wnts to transduce a TCF dependent transcriptional response. Oncogene 1999 Oct 28; 18(44): 5959-5966.
Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol 2001 Jul; 3(7): 683-686.
Liu G, Bafico A, Harris VK, Aaronson SA. A Novel Mechanism for Wnt activation of Canonical Signaling through the LRP6 receptor. Mol. Cell. Biol 2003 August; 23: 5825-5835.
Golan T, Yaniv A, Bafico A, Liu G, Gazit A. The human Frizzled 6 (HFz6) acts as a negative regulator of the canonical Wnt. beta-catenin signaling cascade. J Biol Chem 2004 Apr 9; 279(15): 14879-14888.
Bafico A, Liu G, Goldin L, Harris V, Aaronson SA. An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell 2004 Nov; 6(5): 497-506.
Liu G, Bafico A, Aaronson SA. The mechanism of endogenous receptor activation functionally distinguishes prototype canonical and noncanonical Wnts. Mol Cell Biol 2005 May; 25(9): 3475-3482.
Hall CL, Bafico A, Dai J, Aaronson SA, Keller ET. Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res 2005 Sep 1; 65(17): 7554-7560.
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