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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

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

Contact Info
Office: 843-792-4687

Research Interests

Research in the Howe laboratory is focused on understanding the signaling pathways activated by transforming growth factor β1 (TGFβ1), interleukin-like EMT inducer (ILEI) and Wnt in cellular models of differentiation and cancer. One major area of interest is a recently identified signaling pathway whereby TGFβ regulates epithelial-mesenchymal transitions (EMT) and metastasis through a post-transcriptional mechanism involving the regulation of an RNA binding protein, heterogeneous ribonucleoprotein E1 (hnRNP E1). We are focused on how TGFβ regulation of hnRNP E1 phosphorylation not only regulates translational silencing of select mRNAs involved in EMT/metastasis but also of lncRNAs that may also contribute to tumor progression. Candidate mRNA targets and lncRNAs are actively being pursued and one mRNA target in particular, the cytokine ILEI, has become a major focus of the laboratory. Aside from its known role in EMT, relatively little is known regarding ILEI. We have identified ILEI as a potent stem factor in breast epithelium and are actively investigating the molecular mechanisms through which it mediates its progenitor effects.

In another focus area we are investigating the role of the adaptor molecule, disabled-2 (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. We have also made the recent observation that Dab2 regulates TGFβ-induced apoptosis and autophagy. We have shown that mechanistically Dab2 serves as a molecular switch to control whether cells undergo apoptosis or autophagy in response to TGFβ, and significantly this switch may be underlie chemosensitivity and acquired-resistance during tumorigenesis.  

Recent Publications | Additional Publications

Grelet S, Link LA, Howley B, Obellianne C, Palanisamy V, Gangaraju VK, Diehl JA, and Howe PH. (2017) An hnRNP E1-regulated mRNA to lncRNA splice switch mediates EMT and tumor progression. Nat Cell Bio [Epub ahead of print] PMID:28825698.

Lv Z, Rickman KA, Yuan L, Williams K, Selvam SP, Woosley AN, Howe, PH, Ogretmen B, Smogorzewska A, Olsen SK. (2017) S. pombe Uba1-Ubc15 structure reveals a novel regulatory mechanism of ubiquitin E2 activity. Molecular Cell 65(4):699-714.

Jiang Y, Woosley AN, Sivalingam N, Natarajan S, Howe PH. (2016) Cathepsin-B-mediated cleavage of disabled-2 regulates TGF-β-induced autophagy. Nat Cell Biol Jul 11, doi:10.1038/ncb3388, Epub ahead of print.

Link LA, Howley BV, Hussey GS, Howe PH. (2016) PCBP1/HNRNP E1 protects chromosomal integrity by translational regulation of CDC27. Mol Cancer Res 14(7):634-646.

Brown AS, Mohanty BK, Howe PH. (2016) Identification and characterization of an hnRNP E1 translational silencing motif. Nucleic Acids Res 44(12):5892-5907.

Howley BV, Hussey GS, Link LA, and Howe PH. (2016) Translational regulation of inhibin βA by TGFβ via the RNA-binding protein hnRNP E1 enhances the invasiveness of epithelial-to-mesenchymal transitioned cells. Oncogene 35(13):1725-1735.  PMID: 26096938

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

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

*Hussey GH, Chaudhury A, Dawson AE, Lindner DJ, Knudsen CR, Wilce MCJ, Merrick WC, and Howe PH. (2011) Identification of an mRNP complex regulating tumorigenesis at the translational elongation step. Mol Cell 41(4):419-431. 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. (2011) Myosin II isoform switching mediates invasineness following TGFbeta-induced epithelial-mesenchymal transition. Proc Natl Aca Sci 108(44):17991-17996.

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

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

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

Chaudhury A, Hussey GS, Ray PS, Jin G, Fox PL, Howe PH. (2010) 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.

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

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