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Department of biochemistry and Molecular biology

Philip Howe, PhD

Professor and Chairman
Philip Howe, PhDBiochemistry and Molecular Biology
Hans and Helen Koebig Chair in Clinical Oncology

2001-2011 Staff/Professor, Cell Biology
The Lerner Research Institute, Cleveland Clinic Foundation
1996-2001 Associate Staff/Professor, Cell Biology
The Lerner Research Institute, Cleveland Clinic Foundation
1990-1996 Assistant Staff/Professor, Cell Biology
The Lerner Research Institute, Cleveland Clinic Foundation

2003-2011 Professor, Physiology & Biophysics
Case Western Reserve University
1998-2003 Associate Professor, Physiology & Biophysics
Case Western Reserve University
1992-1998 Assistant Professor, Physiology & Biophysics
Case Western Reserve University

1989-1990 Research Assistant Professor, Cell Biology
Vanderbilt University
1988-1989 Postdoctoral Fellow, Cell Biology
Vanderbilt University


Education
1988   Ph.D., Biochemistry, Medical College of Georgia, Augusta, GA
1978-1979  Faculte de Medecine, Nice, France


Contact Info
Email: howep@musc.edu
Office: 843-792-4687
BSB-501A

Research Interests

The central objective of the research in my laboratory is to understand the signaling pathways activated by transforming growth factor β1 (TGFβ1) and Wnt and their potential cross-talk in cellular models of differentiation and cancer. Several specific research areas are under investigation.

Project 1: We have delineated a post-transcriptional regulatory pathway by which TGFβ modulates expression of epithelial mesenchymal transition (EMT)-inducer proteins and EMT itself. We have identified heterogeneous ribonucleoprotein E1 (hnRNP E1) and elongation factor 1A1 (EF1A1) as an mRNP complex that binds to a structural, 33-nucleotide TGFbeta-activated translation (BAT) element in the 3’-UTR of EMT inducer transcripts and represses their translation. We are currently investigating the signaling pathway by which TGFβ regulates this mRNP complex and its role in mediating metastic progression in breast and colon cancers.

Project 2: We are investigating the role of the adaptor molecule, Dab2, as a mediator of the cross-talk between the TGFβ and Wnt signaling pathways. We have shown that the tumor suppressor functions of Dab2 are mediated thru its attenuation of canonical Wnt/β-catenin signaling by selectively recruiting the Wnt co-receptor LRP6 to the clathrin-dependent endocytic route, thereby sequestering it from caveolin-mediated endocytosis and signaling. TGFβ levels in cells and tissues regulates Dab2 expression and thereby regulates, thru Dab2, Wnt signaling. We are currently investigating this cross-talk in the developing zebrafish and in animal tumor models.

Project 3: A third project in the lab focuses on the signaling pathways by which TGFβ mediates apoptosis in B-lymphocyte cells. We have been able to determine that the Smad regulatory proteins mediate TGFβ-induced apoptosis through the induction of the pro-apoptotic protein Bim. TGFβ induces the Smad3-dependent transcription of Bim which heterodimerizes and neutralizes the anti-apoptotic effects of Bcl-2, releasing cytochrome c from the mitochondria and inducing apoptosis through activation of the caspase cascade. Currently we are investigating: the phosphorylation and degradation of Bim protein, and 2) the transcriptional mechansim through which TGFβ mediates Bim induction.

Recent Publications | Additional Publications

Hussey GS, Link LA, Brown AS, Howley BV, Chaudhury A, Howe, PH. Establishment of a TGF beta-induced post-transcriptional
EMT gene signature
. PLoS One 7(12):e52624. doi: 10.1371/journal.pone.0052624, 2012.

Jiang Y, Xi H, and Howe PH. Disabled-2 (Dab2) binds LRP6 and antagonizes Wnt/beta-catenin signaling through clathrin-mediated endocytosis. EMBO J. 31:2336-2349, 2012.

*Hussey GH, Chaudhury A, Dawson AE, Lindner DJ, Knudsen CR, Wilce MCJ, Merrick WC, and Howe PH. Identification of an mRNP complex regulating tumorigenesis at the translational elongation step. Mol. Cell 41(4):419-431, 2011. PMCID: PMC3061437
 *Previewed by Zhang YE. "Stopped in translation: EMT control meets eukaryotic elongation". Dev. Cell 20(3): 289-290, 2011. *Chosen and evaluated by the Faculty of 1000.

Beach JR, Hussey GS, Miller TE, Chaudhury A, Patel P, Monslow J, Zheng Q, Keri RA, Reizes O, Bresnick AR, Howe PH, and Egelhoff TT. Myosin II isoform switching mediates invasineness following TGFbeta-induced epithelial-mesenchymal transition. Proc. Natl. Aca. Sci. 108(44):17991-17996, 2011.

Chaudhury A, Hussey GS, and Howe PH. 3'-UTR-mediated post-transcriptional regulation of cancer metastasis: beginning at the end. RNA Biology 8(4):595-599, 2011.

Hussey GS, Chaudhury A, Dawson AE, Lindner DJ, Knudsen CR, Wilce MC, Merrick WC, Howe PH. Identification of an mRNP complex regulating tumorigenesis at the translational elongation step. Mol Cell. 41(4):419-31, 2011.

Chaudhury A, Chander P, Howe PH. Heterogeneous nuclear ribonucleoproteins (hnRNPs) in cellular processes: Focus on hnRNP E1's multifunctional regulatory roles. RNA. 16(8):1449-62, 2010. Epub 2010 Jun 28. Review.

Chaudhury A, Hussey GS, Ray PS, Jin G, Fox PL, Howe PH. TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nat Cell Biol. 12(3):286-93, 2010. Epub 2010 Feb 14.

Jiang Y, Luo W, Howe PH. Dab2 stabilizes Axin and attenuates Wnt/beta-catenin signaling by preventing protein phosphatase 1 (PP1)-Axin interactions. Oncogene. 28(33):2999-3007, 2009. Epub 2009 Jul 6.

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