Regulation of cell migration by extracellular matrix
Dr. Howe received his PhD in Tumor Cell Biology from Northwestern University in 1996. From 1996 to 2001, he was a postdoctoral fellow at the University of North Carolina at Chapel Hill. In 2001, he received a Howard Temin Career Award from the National Cancer Institute, and stayed at UNC until 2003, when he was recruited to the Vermont Cancer Center and the Department of Pharmacology at the UVM College of Medicine.
We study the molecular machinery that controls cell motility with a special interest in how this machinery is dysregulated during metastasis. Metastatic tumor cells invade their surrounding tissue, migrate through the stroma to nearby blood or lymphatic vessels, and thus gain route to spread to distal sites throughout the body. The processes of invasion and migration involve a number of enzymatic activities that are controlled in a highly localized manner in distinct regions with the cell. Thus, an important question is how are signals that control cytoskeletal dynamics and cell movement regulated in subcellular space?
Research in our lab focuses on the mechanisms through which cells sense and interpret their extracellular environment and the signaling pathways through which these environmental cues control cytoskeletal dynamics and cell movement. Our current interests include the role that the tissue microenvironment plays in the progression and spread of ovarian cancer.
We use a variety of molecular and cellular techniques (e.g. biochemical analysis of signaling cascades, multi-dimensional microscopy) to investigate the pathways used by cells to sense the biochemical and mechanical properties of their extracellular matrix, and the interplay between mechanotransduction and classical second messenger signaling pathways in the regulation of cytoskeletal dynamics and invasive behavior. The lab also has burgeoning interests in using microfluidics and microfabrication to control the cellular microenvironment, the development of novel methods for detecting protein-protein interactions, and the development of experimentally tractable cell culture systems for modeling metastasis and analyzing adhesion-related signaling events during metastatic cell migration.
McKenzie AJ, Campbell SL, Howe AK. Protein kinase A activity and anchoring are required for ovarian cancer cell migration and invasion. PLoS One. 2011;6(10):e26552. Epub 2011 Oct 19
Rivard RL, Birger M, Gaston KJ, and Howe AK. AKAP-independent localization of type-II protein kinase A to dynamic actin microspikes. Cell Motil Cytoskeleton. 2009 Sep;66(9):693-709.
Deming PB, Campbell SL, Baldor LC, and Howe AK. Protein kinase A regulates 3-phosphatidylinositide dynamics during platelet-derived growth factor-induced membrane ruffling and chemotaxis. J Biol Chem. 2008 Dec 12;283(50):35199-211.
Howe, A.K., Baldor, L.C., and Hogan, B.P. Spatial regulation of the cAMP-dependent protein kinase during chemotactic cell migration. Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14320-14325
Howe, A. K. Regulation of actin-based cell migration by cAMP/PKA. Biochim Biophys Acta. 2004 Jul 5;1692(2-3):159-74
Howe, A.K., Aplin, A.E., Juliano, R.L. Anchorage-dependent ERK signaling--mechanisms and consequences. Curr Opin Genet Dev. 2002 Feb;12(1):30-5.
Howe, A.K., Juliano, R.L. Regulation of anchorage-dependent signal transduction by protein kinase A and p21-activated kinase. Nat Cell Biol. 2000 Sep;2(9):593-600.
* indicates equal contribution
Langevin HM, Nedergaard M, Howe AK (2013) Cellular control of connective tissue matrix tension. J Cell Biochem 114(8): 1714-9.
Abbott RD, Koptiuch C, Iatridis JC, Howe AK, Badger GJ, Langevin HM (2013) Stress and matrix-responsive cytoskeletal remodeling in fibroblasts. J Cell Physiol 228(1): 50-7.
Abbott RD, Howe AK, Langevin HM, Iatridis JC (2012) Live free or die: stretch-induced apoptosis occurs when adaptive reorientation of annulus fibrosus cells is restricted. Biochem Biophys Res Commun 421(2): 361-6.
McKenzie AJ, Campbell SL, Howe AK (2011) Protein kinase A activity and anchoring are required for ovarian cancer cell migration and invasion. PLoS One 6(10): e26552.
Cassavaugh JM, Hale SA, Wellman TL, Howe AK, Wong C, Lounsbury KM (2011) Negative regulation of HIF-1α by an FBW7-mediated degradation pathway during hypoxia. J Cell Biochem 112(12): 3882-90.
Caldwell GB, Howe AK, Nickl CK, Dostmann WR, Ballif BA, Deming PB (2012) Direct modulation of the protein kinase A catalytic subunit α by growth factor receptor tyrosine kinases. J Cell Biochem 113(1): 39-48.
Howe AK (2011) Cross-talk between calcium and protein kinase A in the regulation of cell migration. Curr Opin Cell Biol 23(5): 554-61.
Nat'l Cancer Institute - Howard Temin Career Award The goal of the National Cancer Institute's (NCI) Howard Temin Award is to bridge the transition from a mentored research environment to an independent
basic cancer research career for scientists who have demonstrated unusually high potential during their initial stages of training and development. This special award is aimed at fostering the research careers of outstanding junior scientists in basic research who are committed to developing research programs directly relevant to the understanding of human biology and human disease as it relates to the etiology, pathogenesis, prevention, diagnosis, and treatment of human cancer. The major objective of the award is to sustain and advance the early research careers of the most promising M.D.s and Ph.D.s while they consolidate and focus their independent research programs and obtain their own research grant support. To achieve this objective, the Howard Temin Award offers candidates up to five years to gain additional skills and knowledge in human cancer research during a period of one to three years in a mentored environment, followed by transition to the equivalent of a junior faculty position to develop an independent research program. (2001 - 2006)
Department of Pharmacology
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