Philip Howe

Professor

Ph.D., Medical College of Georgia, 1988
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Transforming Growth Factor Beta (TGFβ) and Wnt Signaling Pathways

RESEARCH DESCRIPTION

The objective of the research in my laboratory is to understand the signaling mechanism of transforming growth factor β1 (TGF β1). Several specific research areas are under investigation.

We are investigating the role of the adaptor molecule, Dab2, in several differentiation models; a TGFβ-mediated epithelial to mesenchymal transdifferentiation model in mouse mammary epithelial cells and in an in vitro model for visceral endoderm differentiation in embryonic stem cell like F9 teratocarcinoma cells. In both cases we observe that Dab2 protein expression is induced during the differentiation process and we are investigating two potential mechanism for this induction. 1) post-translational mechanism; we observe that although Dab2 protein expression levels are dramatically increased during the differentiation process, Dab2 mRNA levels are relatively stable and thus cannot account for the c observed hanges in protein levels. We are currently determining whether these increases in Dab2 protein levels are due to increased translation of the Dab2 mRNA during the differentiation process and if so through what molecular mechanism 2) protein degradation levels; we have established that Dab2 protein levels are increased during the differentiation process and that one mechanism through which this occurs is through an inhibition of Dab2 protein degradation. We are currently investigating the degradation of Dab2 protein with specific emphasis on its GSK3β-dependent phosphorylation and subsequent ubiquitination and degradation thru the proteasomal degradation pathway.

A second project focuses on the signaling pathways by which TGFβ mediates apoptosis in B-lymphocyte cells. We have recently demonstrated that the pro-apoptotic protein Bim is a molecular mediator of TGFβ-induced apoptosis in these cells. 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. Two projects are currently investigating 1) the phosphorylation and degradation of Bim protein and 2) the transcriptional mechansim through which TGFβ mediates Bim induction.

RELATED RESEARCH AREAS

View Philip Howe's Publications on PubMed